GPCRs: Gi and Gs

GPCR = G-protein coupled receptor

Gi = G inhibitory alpha subunit

Gs = G stimulatory alpha subunit

Are there structural differences between Gi and Gs subunits (secondary structure)? Or is it just categorization by effect on cAMP level? (Gi inhibits cAMP production, while Gs stimulates cAMP production)

Gi and Gs have a structurally different sub unit in their alpha chain.

The receptors for PGE1 and adenosine interact with inhibitory Gi, which contains the same β and γ subunits as stimulatory Gs but a different α subunit (Giα). In response to binding of an inhibitory ligand to its receptor, the associated Gi protein releases its bound GDP and binds GTP; the active Giα · GTP complex then dissociates from Gβγ and inhibits (rather than stimulates) adenylyl cyclase.

Both β1- and β2-adrenergic receptors are coupled to G proteins (Gs), which activate adenylyl cyclase. In contrast, α1 and α2 receptors are coupled to two other G proteins, Gq and Gi, respectively. Gi inhibits adenylyl cyclase, and Gq stimulates phospholipase C to generate IP3 and DAG as second messengers.

Also this,

A comparison of chimeric receptor 1, which interacts with Gs, and chimeric receptor 3, which interacts with Gi, shows that the G protein specificity is determined primarily by the source of the cytosol-facing loop between α helices 5 and 6. A comparison of chimeras 1 and 2 indicates that α helix 7 plays a role in determining the ligand-binding . B. Kobilka et al., 1988, Science 240:1310; W. A. Catterall, 1989, Science 243:236.

I'd recommend reading through this:

Cross-communication between Gi and Gs in a G-protein-coupled receptor heterotetramer guided by a receptor C-terminal domain

G-protein-coupled receptor (GPCR) heteromeric complexes have distinct properties from homomeric GPCRs, giving rise to new receptor functionalities. Adenosine receptors (A1R or A2AR) can form A1R-A2AR heteromers (A1-A2AHet), and their activation leads to canonical G-protein-dependent (adenylate cyclase mediated) and -independent (β-arrestin mediated) signaling. Adenosine has different affinities for A1R and A2AR, allowing the heteromeric receptor to detect its concentration by integrating the downstream Gi- and Gs-dependent signals. cAMP accumulation and β-arrestin recruitment assays have shown that, within the complex, activation of A2AR impedes signaling via A1R.


We examined the mechanism by which A1-A2AHet integrates Gi- and Gs-dependent signals. A1R blockade by A2AR in the A1-A2AHet is not observed in the absence of A2AR activation by agonists, in the absence of the C-terminal domain of A2AR, or in the presence of synthetic peptides that disrupt the heteromer interface of A1-A2AHet, indicating that signaling mediated by A1R and A2AR is controlled by both Gi and Gs proteins.


We identified a new mechanism of signal transduction that implies a cross-communication between Gi and Gs proteins guided by the C-terminal tail of the A2AR. This mechanism provides the molecular basis for the operation of the A1-A2AHet as an adenosine concentration-sensing device that modulates the signals originating at both A1R and A2AR.


Xinming Wang 1,2 , Abishek Iyer 3 , A. Bruce Lyons 4 , Heinrich Körner 1,5 * † and Wei Wei 1 * †
  • 1 Key Laboratory of Anti-inflammatory and Immune Medicine, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Institute of Clinical Pharmacology, Ministry of Education, Anhui Medical University, Hefei, China
  • 2 Department of Pharmacy, First Affiliated Hospital of Anhui Medical University, Hefei, China
  • 3 Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
  • 4 School of Medicine, University of Tasmania, Hobart, TAS, Australia
  • 5 Menzies Institute for Medical Research, University of Tasmania, Hobart, TAS, Australia

Macrophages have emerged as a key component of the innate immune system that emigrates to peripheral tissues during gestation and in the adult organism. Their complex pathway to maturity, their unique plasticity and their various roles as effector and regulatory cells during an immune response have been the focus of intense research. A class of surface molecules, the G-Protein coupled receptors (GPCRs) play important roles in many immune processes. They have drawn attention in regard to these functions and the potential for therapeutic targets that can modulate the response of immune cells in pathologies such as diabetes, atherosclerosis, and chronic inflammatory diseases. Of the more than 800 GPCRs identified, 񾄀 are currently targeted with drugs which have had their activity investigated in vivo. Macrophages express a number of GPCRs which have central roles during cell differentiation and in the regulation of their functions. While some macrophage GPCRs such as chemokine receptors have been studied in great detail, the roles of other receptors of this large family are still not well understood. This review summarizes new insights into macrophage biology, differences of human, and mouse macrophages and gives details of some of the GPCRs expressed by this cell type.

C6. G Protein Coupled Receptors (GPCR) and G proteins

  • Contributed by Henry Jakubowski
  • Professor (Chemistry) at College of St. Benedict/St. John's University

Receptors that interact with G proteins (G protein coupled receptors or GPCRs) have common characteristics. GPCRs are single polypeptides which have 7 membrane-spanning &alpha - helices. Over 800 similar GPCR receptor genes are found in humans, each encoding a protein of similar topology, but which bind different ligands. Many of the receptors bind to unknown ligands, and hence are called orphan receptors.

The &beta-adrenergic receptor is a prototypical GPCR. Found in muscle, liver, and fat cells, it bind epinephrine and adrenaline which leads to energy mobilization and muscle activation (i.e. flight or fight response). The mechanism of activation of a GPCR is illustrated using the beta adrenergic receptor as an example. The unoccupied adrenergic receptor is associated with a heterotrimeric G protein, which contains an &alpha, &beta,and&gammasubunits. GDP is usually bound to the &alphasubunit. When the hormone is bound to the receptor, interactions of the receptor with the G protein (probably through the &betaand&gammasubunits leads to conformational changes in the G protein leading to replacement of GDP with GTP. This promotes dissociation of the &alphasubunit (with bound GTP), which is then free to bind modulate the activity of an adjacent membrane protein, adenylate cyclase. The &alphasubunit is held to the membrane through a lipid anchor attached through a post-translational modification. As long as GTP remains bound to the G&alpha subunit, it will continue to modulate the activity of adenylate cyclase. A built in regulatory mechanism does exist in the protein since the G&alpha subunit has GTPase activity. The GTP will eventually hydrolyze, the GDP-G&alpha subunit will lose affinity for its bound partner (adenylated cyclase), and return to the heterotrimeric G protein associated with the unbound receptor.

GPCRs appear to bind ligand in a binding cavity localized at the extracellular face and between four of the transmembrane helices. Upon binding of a natural ligand, a conformational change in the arrangement of the helices occurs, allowing access of the G&alpha subunit to the GPCR. In the ternary complex of GPCR:Ligand:G protein, the affinity of the GPCR for the agonist and of the G&alpha subunit for GTP (over GDP) are increased.

The activity and structure of GPCRs have been studied using natural ligands (hormones and neurotransmitters), as well as agonists, partial agonists, inverse agonists and antagonists. As discussed previously, agonists bind to the natural ligand binding site and elicit the same or a partial response (partial agonist). Inverse agonists bind and lower the response of the constituitively active receptor, and antagonists bind and prevent the normal response of an agonist. The figure below shows a crystal structural of the beta-andrenergic:Gs complex with bound agonist.

Figure: Beta-andrenergic:Gs complex (Image made with VMD )

Updated Beta andrenergic receptor Jmol14 (Java) | JSMol (HTML5)

Updated Beta andrenergic receptor:Gs Complex Jmol14 (Java) | JSMol (HTML5)

Updated Models of the GPCR- Melancortin 4 Receptor Jmol14 (Java) | JSMol (HTML5)

Some bacterial toxins work by inactivating the GTPase activity of the G&alpha subunit, keeping it in the "stuck" position. For example, cholera toxin, an enzyme released by Vibrio cholerae , catalyzes the ADP ribosylation of an Arg in the G &alpha subunit by transferring everything but the nicotinamide from NAD+ to the Arg residue.

In contrast to the beta-adrenergic receptor, some G&alpha subunits actually inhibit adenylate cyclase when bound. These G&alpha subunits are called G a i/o in contrast to the stimulatory subunits, G a s. G &alpha subunits interact with proteins other than adenylate cyclase. We have already seen an example with the PKC activation of phospholipase C which is activated by the G a q11 . There are many different G&alpha-like subunits expressed in different tissues. Four structural classes and at least twenty variants of G a have been found.

Examples of different signals, receptors, G&alpha like-subunits, second messenger changes, and affected intracellular enzymes
signal vasopressin epinephrine light odorant odorant sweet tastant
receptor VR &beta-adrenergic rhodopsin odorant recep. 1 odorant recept. 2 sweet receptor
Ga like- subunit Gi Gs transducin Golfactory Golfactory Ggustatory
coupled enzyme adenylate cyclase adenylate cyclase phosphodiesterase phopholipase C adenylate cyclase adenylate cyclase
2nd messenger decrease cAMP increase cAMP decrease cGMP increase IP3 increase cAMP increase cAMP
protein affected decrease PrK-A increase PrK-A dec. Ca, Na perm. inc. Ca perm inc.Ca, Na perm dec. K perm

Another variant of a GDP/GTP binding protein is ras. Mammalian cells contain 3 variants of ras: H, K, and N. They all bind GDP/GTP and have GTPase activity, and are members of a large family of small GTPase proteins. This protein is targeted to the cell membrane through the post-translational addition of a hydrophobic farnesyl group. When activated by binding to GTP, it can to and activated a protein call Raf-1, which is activated to become a tyrosine kinase.

Structure of GPCRs

Members of the GPCR superfamily share the same basic architecture of 7TM α-helices, an extracellular amino-terminal segment and an intracellular carboxy-terminal tail. These plasma membrane-bound receptors have evolved to recognize a diversity of extracellular physical and chemical signals, such as nucleotides, peptides, amines, Ca 2+ and photons. On recognition of such signals, the GPCRs act as proximal event in signaling pathways that influence a wide variety of metabolic and differentiated functions. 10 , 11 An extensive analysis of about 200 GPCR sequences revealed that total length of GPCRs can vary between 311 and 𢏁,490 amino acid residues. The largest variations in length are found in the N and C termini with size up to 879 and 371 amino acid residues, respectively. 18 GPCRs are not only encoded by eukaryotic genes but also by viral genes. Human GPCRs genomic genes are predominantly intronless. 18

The 7TM α-helices connected by three intracellular and three extracellular loops. The extracellular loops of the GPCR can be glycosylated and contain two highly conserved cysteine residues, which build disulfide bonds to stabilize the receptor structure. GPCRs contain extracellular N-terminus domains (ECL1, ECL2 and ECL3) of variable size, ranging from 154 residues (calcitonin receptor) to 36 residues (rhodopsin receptor). This domain contains asparagines residues and motifs for N-glycosylation, which influences intracellular trafficking of receptors to the plasma membrane, and cysteine residues in ECL1 and ECL2 loops that can influence protein folding critical for trafficking of a function receptor to the cell surface. 19 The N terminus of some GPCRs is involved in ligand binding, activation and downregulation. The 7TM α-helices helices of GPCRs are arranged to form a tight, ring-shaped central core that is highly hydrophobic in nature. Similar to most TM proteins, the hydrophobic amino acid residues are presumably arranged to face the lipid bilayer, whereas the more hydrophilic amino acid residues face towards the core. Furthermore, helix-helix interaction contributes to the functional tertiary structure of the GPCRs necessary for receptor folding and stability, ligand binding and ligand-induced conformational changes for G protein coupling. Thus, mutations in the TM domain can have an array of deleterious effects.

GPCRs contains an intracellular carboxyl-terminal domains (ICL1, ICL2 and ICL3) which are involved in several aspects of GPCR signaling. This domain contains Ser and/or Tyr residues which serve as sites for G protein receptor kinase-mediated phosphorylation and receptor desensitization. Some GPCRs contain a cysteine residue in the C-terminal domain, which can serve as site for palmitoylation. This can create a fourth IL (intracellular loops) because of the ability of the palmitoylated cysteine to insert in the plasma membrane. Also, C terminus may be involved in the interactions with other proteins that mediate GPCR signaling, such as the calcyon, PDZ domain-containing proteins, and Homer/Vesl proteins. 19 The GPCR vary not only in sequence, but also in length of amino acid and carboxy-termini (especially the C3 loop). The serine residue at carboxy terminus region of GPCRs gets phosphorylated by G protein-coupled receptor kinases (GRKs). GRKs constitute of six mammalian Ser/Thr protein kinase that phosphorylate agonist-bound, or activated, GPCR as their primary substrates, GRK-mediated receptor phosphorylation rapidly initiates profound impairment of receptor signaling, or desensitization. 20 While the X-ray crystal structures of several GRKs have been solved, but the mechanism of GRK interaction with GPCRs was not known. Recently, Pao et al. (2009) 21 proposed a mechanism whereby the N-terminus of GRK2 protein forms an intramolecular interaction that selectively enhances the catalytic activity of the kinase towards GPCR substrates.

Recently, Sheerer et al. (2008) 22 reported the 3.2 angstrom (A°) crystal structure of the bovine GPCR (opsin) in its G-protein-interacting conformation. (Ops-GalphaCT peptide complex). Perk et al. (2008) 23 reported the crystal structure of ligand-free native GPCR (opsin) from bovine retinal rod cells at 2.9 A° resolution. Compared to GPCR rhodopsin, opsin showed some structural changes in the conserved E(D)RY and NPxxY(x)5,6F regions and in TM5–TM7. At the cytoplasmic side, TM6 was found to be tilted outwards by 6𠄷 A°, whereas the helix structure of TM5 was more elongated and close to TM6. The authors have suggested that the opsin structure sheds new light on ligand binding to GPCRs and on GPCR activation. 23

Animated Lessons Included

/>General Overview and GPCR Structure/Function Relationship | An introduction to GPCRs and examination of their structure/function relationship. />Heterotrimeric G-Protein Structure/Function Relationship | The three subunits, alpha, beta, and gamma are introduced and heterotrimeric G-protein structure/function relationship discussed. />Heterotrimeric G-Protein Targets | The two main targets of heterotrimeric G-proteins are adenylate cyclase and phospholipase C (PLC). />Adenylate Cyclase and Protein Kinase A (PKA) | Adenylate cyclase structure, cAMP production, and protein kinase A (PKA) structure/function relationship. />Phospholipase C (PLC), IP3, and DAG | Part 1 | A comparison of the molecular structures of the different types of phospholipids used in PLC signaling pathways. />Phospholipase C (PLC), IP3, and DAG | Part 2 | PLC-beta cleaves PIP2 into IP3 and DAG. IP3 binds to the IP3-receptor in the membrane of the smooth ER, resulting in the release of calcium into the cytosol, and the recruitment of PKC to the membrane. />Example: Regulation of Blood-Glucose | Part 1 | This lesson puts into context all of the key players introduced throughout this module by examining an example pathway in detail: Regulation of blood-glucose concentration by the hormone glucagon. />Example: Regulation of Blood-Glucose | Part 2 | This continuation of Part 1 introduces phosphorylase kinase, glycogen synthase, and glycogen phosphorylase.

GPCRs (G-protein [guanine nucleotide-binding protein]–coupled receptors) play a central physiological role in the regulation of cardiac function in both health and disease and thus represent one of the largest class of surface receptors targeted by drugs. Several antagonists of GPCRs, such as βARs (β-adrenergic receptors) and Ang II (angiotensin II) receptors, are now considered standard of therapy for a wide range of cardiovascular disease, such as hypertension, coronary artery disease, and heart failure. Although the mechanism of action for GPCRs was thought to be largely worked out in the 80s and 90s, recent discoveries have brought to the fore new and previously unappreciated mechanisms for GPCR activation and subsequent downstream signaling. In this review, we focus on GPCRs most relevant to the cardiovascular system and discuss traditional components of GPCR signaling and highlight evolving concepts in the field, such as ligand bias, β-arrestin–mediated signaling, and conformational heterogeneity.

Heart failure (HF)—a clinical condition resulting from the inability of the heart to sufficiently pump blood to meet the needs of the body—is a prevalent disease leading to high morbidity and mortality. It affects ≈6.5 million American adults and leads to 30 billion USD healthcare expenditure per year. 1 Importantly, the 1- and 5-year mortality rate after HF hospitalization approaches 20% and 40%, 1 and, therefore, understanding the fundamental mechanisms underlying the development of HF an imperative.

HF is most commonly caused by diseases, such as chronic hypertension, myocardial infarction because of coronary artery disease, cardiomyopathic processes, valvular heart disease, or viral myocarditis. 2 These stimuli lead to impaired blood ejection or ventricular filling. 3 From a cardiac performance perspective, HF is characterized as HF with reduced ejection fraction (also known as systolic HF) and caused by a failure of cardiac contraction or HF with preserved ejection fraction (also known as diastolic HF) with normal cardiac contraction but impaired filling. 3 Both types of HF are associated with structural or functional abnormalities of the left ventricle that is primarily induced by the enlargement of cardiomyocytes as either an increase in cell length, width, or both, referred to as hypertrophic growth. Cardiomyocyte hypertrophy is initiated by a variety of intrinsic and extrinsic stimuli, such as mechanical stress, hormones, cytokines, and growth factors that are sensed by cardiomyocytes through a broad array of receptors on the cell membrane. 4 Among the various surface receptors, a class of considerable importance is the family of GPCRs (G-protein [guanine nucleotide-binding protein]–coupled receptors), also known as 7TMRs (7-transmembrane receptors), which represents the largest and the most versatile family of cell surface receptors. 5 GPCRs play important roles in a wide variety of physiological processes and, not surprisingly, are commonly targeted for medicinal therapeutics. For instance, chronic activation of βARs (β-adrenergic receptors) and AT1Rs (Ang II [angiotensin II] type 1 receptors) by their endogenous ligands, norepinephrine and Ang II, respectively, increases the workload of the heart, leading to detrimental effects, such as myocyte death and maladaptive cardiac remodeling. 6 Therefore, drugs that block activation of these receptors, such as β-blockers, Ang II receptor blockers, and ACE (angiotensin-converting enzyme) inhibitors, are widely used in the treatment of HF. In this article, we will provide an overview of GPCR signaling, highlight the function of cardiac GPCRs in the most important cardiovascular cell types, and provide insights into our new appreciation for the complexity of GPCR signaling that has important implications when considering the development of future HF therapeutics.

Overview of GPCR Signaling

G-Protein–Mediated GPCR Signaling

In the classical paradigm, GPCRs transduce signaling through G proteins. G proteins are named for their ability to bind the nucleotides GTP and GDP. They act as molecular switches in transduction of intracellular signaling: when G proteins are bound to GTP, they are active (on) and when bound to GDP, they are inactive (off). 7 Heterotrimeric G proteins are composed of α, β, and γ subunits. When an external signaling molecule binds a GPCR, it causes (or stabilizes) a receptor conformational change, triggering the recruitment of G proteins on the plasma membrane to exchange GDP for GTP on the Gα subunit leading to its activation. GDP-GTP exchange leads to the dissociation of the heterotrimeric G protein into 2 units: the GTP-bound Gα subunit and the dimeric Gβγ complex. Both can interact with a variety of signaling effectors, such as enzymes that produce second messengers and ion channels. The catalytic Gα subunit will hydrolyze the bound GTP to GDP, leading to its reassociation with the Gβγ subunits and termination of the G-protein activation cycle (Figure 1).

Figure 1. Scheme of GPCR (G-protein–coupled receptor) signaling. On agonist ligand binding, GPCRs interact with heterotrimeric G proteins (guanine nucleotide-binding proteins). G proteins undergo a GDP-GTP exchange on the α subunit, leading to the dissociation of the α and βγ subunits and subsequent activation of downstream signaling effectors. G-protein–activated PKC (protein kinase C) and PKA (protein kinase A) in turn phosphorylates the receptor and turns off the G-protein signaling (heterologous desensitization, red line, and phosphate). GRK (GPCR kinase)-mediated GPCR phosphorylation leads to the recruitment of β-arrestins, resulting in desensitization by sterically interdicting G-protein interaction (homologous desensitization, purple line, and phosphate) and subsequent receptor internalization and ubiquitination. β-arrestin engagement with the receptor also initiates the activation of β-arrestin–mediated signaling. AC indicates adenylate cyclase AKT, a serine/threonine kinase also known as protein kinase B DAG, diacylglycerol EGFR, epidermal growth factor receptor IP3, inositol-1,4,5-trisphosphate MAPK, mitogen-activated protein kinase PI3K, phosphoinositide 3-kinase PIP2, phosphatidylinositol 4,5-bisphosphate and PLC, phospholipase C.

Currently, there are 21 Gα subunits, 6 Gβ subunits, and 12 Gγ subunits. 7 Heterotrimeric G proteins are typically referred to by their Gα subunits and divided into 4 main classes: Gαstimulatory (Gαs), Gαinhibitory (Gαi), Gαq, and Gα12/13. 7 This diversity in G-protein subfamilies allows for their distinct regulatory function in signaling transduction. The Gαs stimulates the effector enzyme, adenylyl cyclase, to produce the second messenger cAMP, leading to activation of PKA (protein kinase A) and phosphorylation of a wide variety of intracellular proteins that regulate cellular responses. 8 In contrast, Gαi has an inhibitory effect on adenylyl cyclase, therefore, dampening intracellular cAMP. 9 Gαq activates PLC (phospholipase C) leading to the cleavage of the membrane-bound phosphatidylinositol 4,5–bisphosphate to the second messengers inositol 1,4,5–triphosphate and diacylglycerol. Inositol 1,4,5–triphosphate promotes Ca 2+ release from endoplasmic reticulum. Increased intracellular Ca 2+ and diacylglycerol diffused from the plasma membrane will activate PKC (protein kinase C) stimulating cellular signaling. 9,10 The G proteins Gα12/13 are known to activate the small GTPase Rho. 11

In addition to cell surface receptors, GPCRs localized to other cellular compartments to activate downstream signaling. For instance, the β2AR (β2-adrenergic receptor) activates Gαs to promote cAMP production in early endosomes 12 the β1AR (β1-adrenergic receptor) on cardiomyocyte nuclear membrane acts to activate adenylyl cyclase 13 ET (endothelin) stimulates the nuclei-localized ET receptors to modulate nuclear Ca 2+ concentration 14 and the nuclear α1AR (α1-adrenergic receptor) stimulates inside-out signaling to activate ERK (extracellular signal-regulated kinase) localized to plasma membrane caveolae. 15

GPCR Desensitization

Although GPCR signaling is essential for normal cellular function, sustained signaling can have detrimental effects on cell survival and maladaptive consequences, such as cardiac failure or tumorigenesis. 16,17 Thus, tightly regulated termination of GPCR signaling is critical to maintain normal physiology. Several mechanisms are involved in the termination of receptor signaling, including the abovementioned G-protein inactivation, as well as receptor desensitization that uncouples the receptor from signaling even in the presence of a ligand. The process of receptor desensitization involves phosphorylation of the GPCR at certain serine and threonine residues on the third ICL (intracellular loop) and the carboxy-terminal tail (C terminus) and is termed heterologous and homologous desensitization, respectively. 18 Heterologous desensitization is mediated by kinases activated by receptor-triggered second messenger signaling, such as PKA and PKC, which in turn phosphorylate amino acid residues primarily located within the third ICL and proximal C terminus, to uncouple their associated G proteins and thereby terminating signaling. 18 PKA-mediated phosphorylation can also switch the receptor coupling to a distinct subtype of G proteins. For instance, PKA-mediated phosphorylation of the β2AR decreases the receptor affinity to Gαs, while promoting receptor coupling to Gαi, 19 thus triggering Gαi-mediated pathways and turning off Gαs-activated cAMP production. In addition to inhibition of cAMP production, PKA- or PKC-mediated phosphorylation of cardiac βARs also promote degradation of cAMP by inducing the recruitment of the adaptor protein β-arrestin and PDE4 (phosphodiesterase 4). 20 PDE4 is an important enzyme regulating βAR desensitization through hydrolyzing cAMP to maintain equilibrium of cAMP production and degradation under prolonged receptor stimulation 21 and through enhancing PKA-mediated βAR phosphorylation and subsequent Gs-Gi switching. 22 In contrast, homologous desensitization refers to another key mechanism by which GPCR desensitization occurs and involves receptor phosphorylation through a family of kinases known as GRKs (GPCR kinases). 23 There are 7 members in the GRK family. Among them, GRK1 and GRK7 are specifically expressed in retina GRK4 shows localized expression in spermatozoa and germinal cells, whereas the other 4 members (GRK 2, 3, 5, and 6) are ubiquitously expressed. 23 GRKs mediate phosphorylation of serine and threonine residues primarily within the carboxyl tail of agonist-activated GPCRs and promote translocation of β-arrestin to the receptor. In addition to the GPCR-β-arrestin complex formation dependent on receptor tail phosphorylation, β-arrestin can also be activated by its transient engagement with GPCR transmembrane core. 24

The binding of β-arrestin sterically interdicts further G-protein coupling to the receptor while promoting internalization of the activated receptor. 25 β-arrestins interact with clathrin itself and the clathrin adaptor protein AP2 (adaptor protein 2), therefore, target the attached receptor to the clathrin-coated pits and lead to receptor internalization. 26 Internalized receptors in early endosomes are rapidly recycled to the plasma membrane, or undergo prolonged internalization to late endosomes, from where they can be slowly recycled to the cell surface or proceed to lysosomes for degradation. 9 Interestingly, recent studies suggest that the internalized GPCRs may continue to activate downstream pathways in endosomes leading to sustained signaling. 12,27

β-arrestins may also regulate receptor internalization and degradation by regulating the ubiquitination of the receptors. β-arrestins can directly interact with an array of ubiquitin ligase and deubiquitinases, allowing a finely tuned regulation of the dynamics of ubiquitination/deubiquitination that determines the trafficking destination of the internalized receptors. 28

Β-Arrestin–Mediated GPCR Signaling and the Concept of Biased Agonism

β-arrestins are members of the arrestin family (arrestin 1–4). Arrestin1 and arrestin4 are expressed in retina, whereas arrestin2 (also named β-arrestin1) and arrestin3 (β-arrestin2) are widely expressed in other tissues. 29 The 4 arrestin proteins share a high sequence and structural homology consisting of N- and C-terminal domains built of antiparallel β-strands and intervening loops. 30,31 Despite their highly conserved structure, it seems that the 2 β-arrestin isoforms are sufficient to regulate the diverse array of agonist-activated GPCRs. 29

β-arrestins are critical regulators of GPCR signaling that not only mediate desensitization and internalization of activated receptors but also function as signal transducers through their function as adaptor/scaffold proteins to activate a broad array of intracellular signaling pathways. For instance, β-arrestins can directly interact with the tyrosine kinase c-Src, leading to the formation of receptor-Src complexes and triggering the activation of ERK. 32 They mediate the transactivation of the EGFR (epidermal growth factor receptor) by β1 AR and AT1Rs, which also leads to the ERK activation. 33,34 β-arrestin–dependent ERK activation can regulate protein synthesis through MAPK (mitogen-activated protein kinase) interacting MNK1 (serine/threonine kinase 1), 35 as well as mediate the antiapoptotic signaling by regulating the phosphorylation of BAD (BCL2-associated agonist of cell death). 36 β-arrestins are also involved in cellular processes that initiate PI3K (phosphoinositide 3-kinase) and AKT signaling to lead to various cellular and physiological responses in the context of distinct GPCRs. 37–39 They inhibit the NF-κB (nuclear factor-κB)–targeted gene expression through binding to and stabilizing IκBα—the inhibitor of NF-κB. 40

β-arrestin–mediated signaling seems to be kinetically and functionally divergent from that mediated by G proteins. Whereas G-protein signaling is rapid and transient, β-arrestin signaling is slower and more persistent. 41 For example, G-protein–mediated activation of the ERK leads to its translocation into cell nucleus, where it phosphorylates and activates a variety of transcription factors. In contrast, the ERK activated through β-arrestin is retained in the cytosol, phosphorylating a distinct set of substrates and leading to different cellular responses. 41,42

The ability of β-arrestins to independently transduce cellular signaling has led to the emerging concept known as biased agonism, which describes the ability of different ligands for one GPCR to activate distinct subsets of downstream signaling events. 43 When β-arrestin was originally identified as a mediator of signaling, the prevailing concept at the time was that the binding of ligands to the orthosteric site of a GPCR will signal equally through G-protein– and β-arrestin–dependent pathways, that is, have balanced efficacy toward these two signaling cascades. Under this notion, ligands are classified into full agonists, partial agonists, inverse agonists, and neutral antagonists for both pathways. 44 However, accumulating evidence has now led to a refinement of this conceptual framework whereby a given ligand can potentially activate a receptor to selectively engage either a G protein or β-arrestin as its transducer and stimulate only a subset of downstream signaling. 44 Indeed, a biased ligand can preferentially activate β-arrestin signaling without activating, or even blocking, the G-protein pathway or vice versa. 44 These ligands are, therefore, termed biased agonists (Figure 2).

Figure 2. Modes of GPCR (G-protein–coupled receptor) signaling. A, Biased agonism of GPCRs and potential clinical implications. Biased agonists selectively activate G-protein– or β-arrestin–mediated signaling pathways. Allosteric modulators bind to distinct sites on the receptor and modulate the activity of orthosteric ligands in various manners. Previous studies suggest that sustained G-protein signaling activated by β1ARs (β1-adrenergic receptors) or AT1Rs (angiotensin II type 1 receptor) is associated with deleterious cardiac effects, whereas β-arrestin signaling may be beneficial for cardiac function. Therefore, β1AR and AT1R β-arrestin–biased agonists and allosteric modulators may block the detrimental G-protein activation while enhancing the cardioprotective effects. B, Scheme of the main features of GPCR structure involved in downstream signaling. Biophysical studies of several GPCRs show how on stimulation certain regions of the receptor are more prone to move allowing the binding of the effectors. In particular, the release of the ionic lock between TM (transmembrane domain) 3 and TM6 is critical for receptor activation ICL (intracellular loop) 2, ICL3, TM5, and TM6 seem mainly involved in G-protein signaling initiation. β-arrestin binds to the receptor in 2 configurations: (1) interacting with the receptor tail to mediate receptor internalization and β-arrestin signaling or (2) interacting with the receptor transmembrane core to desensitize G-protein signaling.

In contrast to ligands that bind to the orthosteric site on the receptor (the primary site where endogenous ligands bind), allosteric ligands bind to a topographically distinct sites and modulate the effects of orthosteric ligands. 45,46 Allosteric modulators can modulate the activity of orthosteric ligands in distinct manners: enhance (positive allosteric modulator), decrease (negative allosteric modulator), simply bind without any effect (silent allosteric modulator), or selectively regulate subsets of downstream signaling (biased allosteric modulator) 47 (Figure 2A).

The concept of biased agonism at the level of the receptor and the discovery of allosteric modulators add important dimensions to our understanding of GPCR pharmacology and provide a framework for drug development that can yield improved therapeutic targeting of GPCRs based on ligand-directed selective signaling profiles. Increasingly, biased agonists are being identified for many GPCRs, and many of them are shown to have distinct physiological consequences from balanced agonists. 48 For instance, the β-arrestin–biased ligands for AT1R, TRV120023, and TRV120027 have been shown to increase cardiomyocyte contractility, promote cell survival signaling, antagonize Ang II-induced blood pressure increase and cardiac hypertrophy, and improve cardiac performance. 49–52 However, 2 recent studies have called into question the notion of β-arrestin–biased signaling. 53,54 Although β-arrestin siRNA knock down methods have been used in multiple studies to document β-arrestin–mediated signaling, recent studies using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat–associated 9) gene editing to abolish β-arrestin1/2 expression in HEK293 cells showed that β-arrestins are dispensable for β2AR-mediated ERK activation. 53 Additionally, several previously identified β-arrestin–biased agonists were unable to induce ERK signaling in zero function G cells where G proteins were deleted by gene editing or blocked by an inhibitor. 54 Collectively, the authors of these 2 studies concluded that G proteins are the genuine drivers of GPCR signaling, whereas β-arrestins play a negligible role. 53,54 To address these seemingly contradictory findings between the studies using CRISPR/Cas9 gene editing and 15 years of previous literature establishing β-arrestin–mediated GPCR signaling in vitro and in vivo, an international consortium of GPCR signaling laboratories comprehensively determined the role of β-arrestin in ERK activation downstream of several GPCRs. 55 A range of approaches were used: multiple CRISPR/Cas9 gene-edited cell lines, siRNA knockdown, overexpression, and biased-agonist stimulation. In rigorous fashion, the data showed that siRNA-mediated β-arrestin knockdown attenuates ERK activation, whereas CRISPR/Cas9-mediated β-arrestin knockout has distinct effects depending on the cell lines and receptors tested. 55 This study clearly demonstrated that the net effect of β-arrestin on ERK activation is determined by the balance of the inhibitory effect on G-protein signaling through receptor desensitization and the potentiating effect through β-arrestin–mediated pathways, which may vary between cell lines and physiological settings. 55 Importantly, prolonged and complete deletion of β-arrestins by CRISPR/Cas9 leads to a cellular rewiring where cell growth and survival depends on the shift toward the activation of G-protein–mediated cellular processes. 55

Structural Basis of GPCR Signaling

Despite the large number of family members and the incredible variety of signaling molecules they bind, GPCRs shared common structural motifs. They consist of 7 α-helical TMs (transmembrane domains), hence their 7TMR name, intervening intracellular and extracellular loop regions, an extracellular N terminus, and an intracellular C terminus. 56

Remarkable progress has been made in the past decade in understanding the biophysical structure of GPCRs, revealing the 3-dimensional conformation of GPCRs and their signaling complexes. One of the most well characterized is the β2AR. In 2011, an active conformation of β2AR in complex with the agonist BI-167107 and the heterotrimeric Gs protein was solved. 57 This structure showed that the intracellular side of the β2AR interacts with the N- and C-terminal α-helices of Gαs. Compared with the inactive state, the β2AR undergoes significant conformational changes on agonist activation: the outward shift of the C terminus of TM5, TM6, and the ICL 3, which forms an interface with the C terminus of the Gαs the formation of a short helix in ICL 2, the second interface for Gαs binding the inward shift of the C terminus of TM7 and the N terminus of helix 8, which may be associated with receptor phosphorylation and β-arrestin recruitment 57 (Figure 2B). A recent structural study of the calcitonin receptor with cryo-electron microscopy revealed a similar interface of the cytoplasmic side of the receptor TM domains with the Gαs, suggesting a conserved receptor G-protein interface among GPCRs. 58

Structural studies have also shed light on the interaction of GPCRs with β-arrestin. The crystal structure of constitutively active rhodopsin in complex with preactivated β-arrestin suggests that β-arrestin first interacts with the C terminus tail of rhodopsin and disrupts the intramolecular interaction of the N and C domain of β-arrestin. 59 This promotes the full interaction of β-arrestin with the receptor intracellular pocket formed by the cytoplasmic side of rhodopsin TM domains. Studies of β2AR-β-arrestin complexes reveal that interaction of β-arrestin the receptor likely occurs in a 2-step process. 25,60 This study used a chimeric receptor, the β2AR with C terminus replaced with the C tail of vasopressin type 2 receptor, which maintains the β2AR pharmacological properties but with a much higher affinity for β-arrestin. 25 Analysis of EM images and 3-D reconstructions revealed that β-arrestin was bound to the receptor in 2 configurations: a weaker interaction involving the phosphorylated C terminus in ≈60% of the complexes and a tighter interaction with finger-loop region of β-arrestin engaged within the transmembrane core of the β2AR (Figure 2B). 25 Interestingly, these 2 receptor-β-arrestin conformations appear to carry out distinct functions, with the tail interaction being able to mediate receptor internalization and β-arrestin signaling, whereas engagement with core conformation is likely needed to interdict G-protein activation, that is, desensitization (Figure 2B). 61

The discovery of biased agonism implies that receptors can adopt multiple active conformations. Conceptually, GPCRs can be considered as oscillating among a variety of intermediate conformational states. 62 Such conformational heterogeneity allows the receptor to differentially interact with distinct ligands and transducers and subsequently signal through a diverse set of pathways. Binding of ligands to the receptor shift the equilibrium of distinct receptor conformations, each ligand preferentially stabilizing unique conformational states that recruit selective signaling transducers. 43 Accumulating evidence support the idea that different ligands stabilize distinct receptor conformations. Using fluorescence spectroscopy, it has been shown that ligands with different efficacy have distinct effects on the conformational change of β2AR, represented by the disruption of 2 molecular switches: ionic lock that links the cytoplasmic ends of TM3 and TM6 and whose disruption is a key feature of receptor activation and a rotamer toggle switch in TM6 that lead to movement of TM6 and receptor activation. 63 Using single-molecule fluorescence resonance energy transfer imaging movement of TM6 in the β2AR was monitored in the presence of different orthosteric ligands with varying efficacies (partial or full agonists) and showed that different agonists distinctively affect TM6 motion of Gs-coupled β2ARs highlighting that a β2AR in complex with Gs is structurally unique from that of the nucleotide-free β2ARs-Gs complex. 64 The concept of ligand-specific receptor conformations has also been studied using chemical labeling and mass spectrometry and identified unique conformational changes of the β2AR when stabilized by a panel of ligands ranging from full agonists to a β-arrestin–biased agonist. 65 These data are consistent with recent studies showing that G-protein– and β-arrestin–biased agonists stabilize distinct conformations for the vasopressin type 2 receptor 66 and cholecystokinin-2 receptor. 67

GPCRs in Cardiovascular Regulation and HF

GPCRs are widely expressed in the cardiovascular system and in a broad array of cell types, such as cardiomyocytes, fibroblasts, endothelial cells (ECs), and vascular smooth muscle cells (VSMCs). In this section, we will highlight several of the most well-studied and therapeutically targeted GPCRs and their regulation in distinct cardiac cell types.

Β Adrenergic Receptors

Among the GPCRs, β1AR and β2AR are the predominant GPCR subtypes expressed in the heart of many mammalian species, including humans, and are the principal regulators of cardiovascular function. 68 Under normal physiological conditions, the β1AR is the most abundant βAR subtype in cardiomyocytes, comprising ≈80% of total βARs, whereas the β2AR comprises ≈20%. The stoichiometry of the 2 βAR subtypes changes to ≈60:40 under conditions of HF, mainly caused by the selective downregulation of β1AR expression. 69

βARs play an important role in the pathophysiology of human heart disease and are common therapeutic drug targets. βARs are traditionally activated by the catecholamine hormone epinephrine and neurotransmitter norepinephrine. They can also be modulated by a variety of pathways, such as vasopressin, 70 insulin, 71 TNF-α (tumor necrosis factor-α), 72 and prostaglandin E. 73 The β1AR primarily couples to Gαs, which activates the signaling effector adenylyl cyclase to promote the second messenger cAMP production and activates PKA, regulating a diverse array of intracellular responses and ultimately an increase in inotropic and chronotropic cardiac function. 69 With biased ligand stimulation, the β1AR may selectively engage Gαi to activate β-arrestin–mediated pathways. 74 The β2AR also primarily couples to Gαs but can also couple to Gαi through a G-protein switching mechanism induced by PKA-mediated receptor phosphorylation. 19 Several studies suggest that excessive β1AR signaling promotes apoptosis of cardiomyocytes, activation of adverse signaling pathways, and exerts detrimental effects on the heart, whereas β2AR signaling has antiapoptotic and cardioprotective effects. 75–77

β-Blockers are one of the most widely used classes of drugs in numerous conditions, especially in cardiovascular diseases, such as hypertension, postacute myocardial infarction, and HF. 78 For example, clinical trials have shown that treatment with the β-blockers, carvedilol, bisoprolol, or metoprolol significantly reduces morbidity and mortality in HF. 79–81 Treatment with β-blockers normalizes βAR signaling by preventing excessive receptor activation and reversing receptor downregulation and improves left ventricular contractile function. The main cardiovascular use of β-blockers is to block deleterious G-protein overactivation in the heart. The main side effects involve bronchial and blood vessel constriction, which are mainly caused by global inhibition of β2ARs in other tissues. 82

The β-blocker carvedilol in particular has been identified as a β-arrestin–biased βAR ligand that preferentially activates β-arrestin–mediated pathways while having inverse agonism toward Gαs signaling. 83,84 Carvedilol-stimulated βAR activates a diverse array of signaling events in β-arrestin–dependent manner, including microRNA processing, transactivation of EGFR, and induction of ERK. 42,84,85 β-arrestin–mediated EGFR transactivation appears to have a cardioprotective effect as shown by increased apoptosis and cardiac dilation in transgenic mice overexpressing a mutant β1AR lacking GRK phosphorylation sites that cannot recruit β-arrestin and, therefore, unable to transactivate EGFRs. 33 Thus, β-arrestin–dependent βAR signaling seems to be beneficial to the heart.

Among the many cell types that compose the mammalian heart, the most abundant are cardiomyocytes, cardiac fibroblasts, ECs, and VSMCs. 86 In the following section, we will discuss unique roles of βARs in the various cell types relevant to cardiovascular pathophysiology (Figure 3A).

Figure 3. Functional roles of GPCRs (G-protein–coupled receptors) in the cardiovascular system. A, Pathophysiological roles of βARs (β-adrenergic receptors) in cardiovascular cells. β1ARs (β1-adrenergic receptors) and β2ARs (β2-adrenergic receptors) are differentially expressed in the cardiovascular system. β1ARs are the predominant βAR subtype in cardiomyocytes, the activation of which increases cardiac contractility and promotes myocyte hypertrophy. β2ARs are most abundant in cardiac fibroblasts, endothelial cells, and vascular smooth muscle cells, where they play important roles in fibrosis and vasodilation. B, Schematic representation of AT1R (angiotensin II type 1 receptor) functions in cardiovascular cell types. AT1Rs regulate a complex array of responses in the cardiovascular system. Chronic AT1R activation promotes hypertrophy, fibrosis, and cardiac remodeling. C, Main effects of the other GPCRs. GPCRs participate at different levels in the regulation of cardiovascular pathophysiology. Each receptor class will have differential effects depending on the receptor subtype, cell type, and mode of stimulation, thus contributing in diverse ways to a specific phenotype. For specific functional roles of individual receptor subtypes, see the Table. αAR indicates α-adrenergic receptor 5-HT, serotonin receptor APJ, apelin receptor AR, adenosine receptor ECM, extracellular matrix eNOS, endothelial NO synthase ETR, endothelin receptor HR, histamine receptor MLCK, myosin light-chain kinase MMP, metalloproteinase MR, muscarinic receptor RXFP, relaxin family peptide receptor S1PR, sphingosine 1-phosphate receptor VR, vasopressin receptor and VSMC, vascular smooth muscle cell.


Cardiomyocytes, accounting for ≈30% of cell number and 70% of cell mass of the mammalian heart, compose the cardiac muscle and provide the contractile force for the heart. 86 When stressed, they undergo hypertrophic and apoptotic responses that can lead to cardiomyopathy and ultimately to HF. While both the β1AR and the β2AR primarily couple to Gαs and are present on cardiomyocytes, they perform distinct effects on signaling pathways and cellular responses. The β1AR is the predominant subtype on cardiomyocytes. The stimulation of β1AR on cardiomyocytes increases cardiac contractility through PKA-mediated phosphorylation of several important regulatory proteins of intracellular Ca 2+ level or myofilament-Ca 2+ sensitivity, such as L-type Ca 2+ channels, ryanodine receptor, phospholamban, and troponin I. 69,87 The mice with cardiomyocyte-specific overexpression of β1ARs developed myocyte hypertrophy at a young age that progressively developed into HF. 88 In contrast, β2AR stimulation exerts inhibitory effect on contractility and protects cardiomyocytes from apoptosis and hypertrophy. 75,87 These distinct functional roles of the receptor subtypes may be attribute to 2 aspects: the β2AR-activated Gαi inhibits adenylyl cyclase while it activates PI3K-AKT pathway 75 and the differential signaling compartmentation. 89 Whereas the effect of β1AR activation is diffusive, the β2AR-induced cAMP accumulation and PKA-mediated protein phosphorylation are localized. 89


Cardiac fibroblasts are the most abundant nonmyocyte cell type in the heart, constituting ≈60% of cell number and 15% of cell mass of the tissue. 90 They play key regulatory roles in cardiac remodeling, fibrosis, and hypertrophy through regulating cell proliferation, producing and remodeling extracellular matrix (ECM), as well as generating the autocrine and paracrine signaling molecules. 91 The β2AR is the highest expressed βAR subtype in cardiac fibroblasts. 91 Stimulation of β2ARs, but not β1ARs, promotes degradation of collagen and induces autophagy. 92 β2ARs also induce ERK activation and cell proliferation through EGFR transactivation. 91

Endothelial Cell

ECs regulate vascular functions, such as permeability, homeostasis, and angiogenesis. 93 Endothelial dysfunction can increase cardiac oxidative stress, promote angiogenesis and fibrosis, and lead to impaired cardiac function in HF. 93 β2ARs, but not β1ARs, are expressed in ECs. 94 β2AR stimulation activates eNOS (endothelial NO synthase) and subsequently promotes NO-dependent vasodilation. 95 In addition, stimulation or overexpression of the β2AR promotes EC proliferation through ERK activation. 96

Vascular Smooth Muscle Cell

The VSMCs are involved in the regulation of vascular contractility and the production of ECM molecules. 97 On stimulation, the β2AR expressed in VSMCs induces cAMP generation and decreases the activity of MLCK (myosin light-chain kinase)—an enzyme that phosphorylates smooth muscle myosin and enhances contractility. 98 Therefore, the cAMP induced by the β2AR in VSMCs decreases contractility and promotes smooth muscle relaxation. It has been reported that β2AR-induced cAMP also inhibits VSMC migration. 99

Angiotensin Receptors

Angiotensin receptors, particularly AT1R, play a pivotal role in heart pathophysiology. Cardiac AT1Rs are upregulated in response to hypertrophic stimuli, with ischemia, and promote adverse maladaptive cardiac remodeling in HF. 69 Ang II—the endogenous ligand for AT1R—is a peptide hormone that regulates several important physiological processes, such as vascular smooth muscle contraction and aldosterone release. It is also a principle component of the renin-angiotensin system—a key regulatory system controlling blood pressure. AT1Rs couple to the Gαq family of G proteins to transduce signaling but also can mediate signaling through Gβγ subunits and β-arrestin. 100,101 Interestingly, recent evidence suggests that for some β-arrestin–dependent signals, AT1Rs need to initially recruit Gαi to the AT1R-β-arrestin complex to fully transduce the signal. 101

AT1R overexpression promotes cardiac fibrosis and cardiac hypertrophy, whereas knockout of AT1Rs shows enhanced cardiac function after myocardial infarction, suggesting that the AT1R has detrimental cardiac effects. Considering its central role in cardiovascular physiology, AT1Rs have become an attractive target for drug development for cardiovascular diseases. 16 ARBs (angiotensin receptor blockers) and ACE inhibitors are widely used in the treatment of HF. Additionally, recent studies in experimental model systems suggest that selective activation of β-arrestin signaling, while blocking G-protein activation downstream of the AT1R, may provide additional benefit compared with current ARBs. 49–52 This has led to the development of AT1R-β-arrestin–biased ligands, such as the β-arrestin–biased ligands TRV120027 and TRV120023. In preclinical studies, TRV120027 has been shown to be able to increase cardiac performance in addition to the positive effect on preserving renal function observed also with conventional ARBs. 49,50 Like ARBs, TRV120027 promotes vasodilation (via inhibition of the G-protein pathway) but also provides the additional benefit of enhancing cardiac contractility (via β-arrestin signaling). Clinical studies have been performed to evaluate the potential of this molecule 102 even though the BLAST-AHF (Biased Ligand of the Angiotensin Receptor Study in Acute Heart Failure) failed in improving clinical status at 30-day follow-up in patients with acute HF, 103 biased ligands still remain an attractive prospect for new drug design. Another member of the β-arrestin–biased ligand family, TRV120023, has been shown to inhibit Ang II-induced cardiac hypertrophy 52 and promote cardiac contractility 51,104 and cardiomyocyte survival after ischemic injury, 51 whereas the β-arrestin–biased ligand, TRV120067, can improve cardiac function through the alteration of the myofilament-Ca 2+ response in a mouse model of cardiomyopathy. 105 All these studies suggest the potential for biased ligands as new therapeutic agents by selectively activating favorable signaling pathways while minimizing untoward activation of G-protein signaling know to be detrimental in cardiovascular disease.

AT1Rs are also known as a mechanosensors. Mechanical stress is a critical regulator of cardiac function and an important stimulus for the development of cardiac hypertrophy. 106 Mechanical stress induces a variety of hypertrophic responses, such as regulating the expression of hypertrophic genes and increasing protein synthesis and the activity of multiple protein kinases. Treatment with AT1R blockers attenuates these mechanical stress-induced hypertrophic responses in cardiac myocytes. 107 Mechanical stress can activate AT1Rs by promoting autocrine release of Ang II by cardiomyocytes, as well as through Ang II-independent pathways. 108,109 Recent studies suggest that mechanical stress directly and specifically activates β-arrestin–biased signaling of AT1Rs, independent of ligands and G proteins, by allosterically stabilizing a unique β-arrestin–biased AT1R conformation. 110,111 Biophysical analysis of the AT1R conformation suggests that, when the receptor is activated by mechanical stretch, TM7 of the AT1R undergoes an anticlockwise rotation that shifts it into the ligand-binding pocket. 112 A recent study suggests that mechanical stress activates AT1R through a mechanism distinct from that activated by β-arrestin–biased ligands, where the receptors specifically engage Gαi to activate β-arrestin signaling. 101 Importantly, mechanoactivated AT1R-mediated β-arrestin–biased signaling seems to be the mechanism by which the Frank-Starling law of the heart uses to generate force. 104

While the effects of Ang II on AT1Rs have been well studied, it is now recognized that the AT2R (Ang II type 2 receptor) subtype plays an important role in cardiovascular physiology. AT2R levels are high in fetal tissue but rapidly decrease with aging, suggesting a more prominent role in developmental processes. Evidence suggests a potential role for AT2R in antagonizing AT1R signaling. In rat cardiomyocytes and fibroblasts, AT2R antagonizes AT1R-induced proliferation. 113 Ang II-induced signaling that in cardiac fibroblasts activates both AT1R and AT2R to regulate cell growth and collagen secretion and is shown to be altered in HF. 114 Nonetheless, the precise role and importance of AT2R in the cardiovascular pathophysiology still remains to be determined.

AT1Rs are expressed in different components of the cardiovascular system (Figure 3B). Depending on the cell type, the stimulated AT1R can elicit the activation of different pathways. 115


In cardiomyocytes, AT1Rs have been shown to affect processes ranging from hypertrophy to apoptosis. Mice overexpressing AT1R specifically in cardiomyocytes display hearts significantly larger than age-matched controls, increased myocyte area, collagen deposition, and atrial natriuretic factor expression. 116 Activation of Gαq signaling has been shown to contribute to the hypertrophic phenotypes. 117 This phenotype is blocked by the AT1R antagonist losartan. 118 Transgenic mice with inducible cardiomyocyte-specific expression of AT1R showed that receptor activation is responsible for blood pressure-independent hypertrophy and cardiac dysfunction. 119 Interestingly, it was recently discovered that an endogenous peptide defined as Ang (1–7) (angiotensin [1–7]), previously known to be a natural Ang II competitive inhibitor, 120 binds the AT1R acting as a β-arrestin–biased ligand, recruiting and activating β-arrestin to promote ERK phosphorylation. 121 In a rat model of cardiac remodeling, Ang (1–7) infusion is sufficient to reduce the left ventricular wall thickness and the end-diastolic pressure. 121 While the positive effect of the Ang (1–7) peptide has been demonstrated previously, 120 it is now becoming clear that some of its action is derived from its properties as an AT1R-biased ligand.

Ang II-stimulated AT1Rs modulate cardiomyocyte apoptosis through multiple pathways. 122,123 Gαq activation largely increases the intracellular Ca 2+ level, which in turn increases intracellular endonuclease activity. 122 In addition, AT1Rs can couple to Gα12/13 to promote the activation of Rho and Rac and, therefore, production of ROS (reactive oxygen species). These will lead to the activation of downstream pathways, such as JNK (c-Jun N-terminal kinase), p38, and MAPK signaling, as well as HSF1 (heat shock factor 1) acetylation and IGF-IIR (insulin-like growth factor II receptor) expression. 123,124 Whereas the deleterious effects of AT1Rs on cardiac function seem to be G protein-dependent, the β-arrestin–mediated AT1R pathway confers cardioprotective effects, such as increased cardiomyocyte contractility.


While cardiac remodeling that occurs as a result of chronic AT1R stimulation is prominently because of effects on cardiomyocytes, fibroblasts also contribute importantly to this process. AT1R activation leads to the transition of cardiac fibroblasts to active myofibroblasts resulting in the production of different components of the ECM, such as collagens, laminin, and fibronectin, and modifying the expression of MMPs (matrix metalloproteinases). 125 This effect is, at least in part, regulated by an increase in TGF-β (transforming growth factor-β) production, which in turn promotes the translocation of Smad proteins to the nucleus driving the production of several profibrotic factors. 126,127 Mice overexpressing AT1R mutant constructs, which are unable to signal via G proteins, display reduced cardiac fibrosis compared with mice that overexpress WT (wild type) AT1R, thereby indicating that the G-protein pathway contributes to fibrosis. 128 However, there is evidence that β-arrestins also contribute to fibrosis in a range of disease settings. 129 Although blocking AT1Rs has been shown to inhibit myocardial fibrosis, 130 the precise contribution of β-arrestins to the development of fibrosis will require additional studies to evaluate the extent to which AT1R-biased agonists contribute to this process.

Endothelial Cell

In ECs, AT1R activation produces several effects, such as ROS production, increased apoptosis, and elevated thrombosis. Ang II stimulation, indeed, promotes eNOS-dependent NO production 131 and exacerbates oxidative stress, 132 leading to endothelial dysfunction—a relevant process in the context of hypertension. AT1R activation in ECs promotes microvascular permeability via an increase in intracellular calcium levels and endothelial dysfunction through activation of the calcium-dependent calpains. 133 Blocking AT1Rs in ECs is, therefore, an attractive therapeutic option and is supported by data showing that ARBs can improve endothelial dysfunction in hypertensive patients. 134

Vascular Smooth Muscle Cell

Changes observed in ECM production by fibroblasts are a key event in vascular remodeling and have implications for VSMC migration and adhesion as well. 135 Ang II modulates vascular remodeling by directly stimulating VSMC to produce ECM components. 115 In vitro, Ang II-stimulated AT1Rs promote PKC and Jak-STAT pathways, ROS production, and EGFR transactivation, 34,101,136 all resulting in the stimulation of the MAPK cascade, 137 as well as RhoA, Rho-kinase, c-fos, c-Src, and JNK. 138,139 Altogether, these signals lead to a switch from a contractile to a proliferative phenotype and subsequent cell growth. 115 The proproliferative effect has also been observed in vivo, where VSMC proliferation induced by vascular injury is strongly reduced in AT1R knockout mice compared with WT and is distinct from the effects mediated by the AT2R. 140 Moreover, in both humans and rats, c-Src mediates Ang II contractile action, and this effect is exacerbated in hypertension. 141 However, Ang II acts not only through the direct action on AT1Rs but also as an indirect effect on several cell signaling cascades by transactivating other receptor tyrosine kinases (PDGFR [platelet-derived growth factor receptor], EGFR, and IGFR [insulin-like growth factor receptor]). Among these, particularly interesting is the EGFR, which actively contributes to Ang II-induced ERK activation in cardiomyocytes and LV hypertrophy in vivo. 142 In vivo, the inhibition of the EGFR transactivation attenuates hypertension and hypertrophy. 142 In VSMCs, Ang II-mediated EGFR transactivation modulates hypertrophy and migration. 143 Moreover, Ang II stimulation in VSMCs drives a robust proinflammatory response inducing ROS production, cytokine release, and upregulation of adhesion molecules and inflammatory genes. 144 Taken together, these studies show the importance of Ang II and AT1Rs in vascular remodeling. Although AT1R-mediated EGFR transactivation seems to be important for cardiomyocyte growth, it may not be a critical in feature driving cardiac fibroblast proliferation. 145

Α Adrenergic Receptors

Similar to βARs, αARs (α-adrenergic receptors) also bind to and are activated by endogenous catecholamines. The αAR family is composed of α1AR (α1A, α1B, α1D) and α2AR (α2-adrenergic receptor α2A, α2B, α2C) subfamilies (Table). 146 α1ARs primarily couple to Gαq to activate PLC, leading to the generation of second messengers inositol 1,4,5–triphosphate and diacylglycerol that subsequently increase intracellular Ca 2+ level. 147 All 3 α1AR subtypes are expressed in the heart. Cardiomyocytes express both α1A and α1B, with α1B being predominant. 147 α1DAR (α1D-adrenergic receptor) is the major α1AR subtype expressed in coronary smooth muscle cells. 148 In response to hypertrophic stimuli or chronical stimulation, the expression of α1A is increased in cardiomyocytes, whereas the levels of α1B and α1D are decreased, with the overall α1AR level unaltered or increased. 147 Unlike other Gq-coupled receptors, such as the AT1R of which the overexpression or chronical activation will exert adverse cardiac effect, α1ARs perform important cardioprotective functions, including physiological hypertrophy, increased contractility, and decreased apoptosis. 149,150 In response to pressure overload by transverse aortic constriction, mice with double knockout of α1A and α1BAR (α1B-adrenergic receptor) had increased apoptosis, worse dilated cardiomyopathy, and reduced overall survival. 151 These data suggest that some caution should be considered when using α1AR antagonists drugs for the treatment of hypertension or prostate disease. Indeed, although the precise mechanism is not entirely clear, the α1AR antagonists doxazosin and prazosin have been associated with increased incidence of HF and mortality in clinical trials. 152,153 In contrast to cardiomyocytes, cardiac fibroblasts do not express α1ARs. 154 The α1BAR is expressed on coronary artery endothelium cells and may regulate vasodilation and angiogenesis. 155

Table. Representative GPCRs in Cardiovascular System

αAR indicates α-adrenergic receptor A1R, adenosine A1 receptor A2aR, adenosine A2a receptor A2bR, adenosine A2b receptor A3R, adenosine A3 receptor APJ, apelin receptor AR, adenosine receptor ET, endothelin ETAR, ETA receptor ETBR, ETB receptor Gαi, Gαinhibitorys, GαstimulatoryRXFP1, relaxin family peptide receptor 1 RXFP2, relaxin family peptide receptor 2 RXFP3, relaxin family peptide receptor 3 RXFP4, relaxin family peptide receptor 4 S1PR1, sphingosine-1-phosphate receptor 1 S1PR2, sphingosine-1-phosphate receptor 2 S1PR3, sphingosine-1-phosphate receptor 3 S1PR4, sphingosine-1-phosphate receptor 4 and S1PR5, sphingosine-1-phosphate receptor 5.

α2ARs couple to Gi to inhibit adenylyl cyclase, reducing the generation of cAMP and decreasing intracellular Ca 2+ level. They occur both presynaptically and postsynaptically. Presynaptic α2ARs are key regulators of sympathetic and catecholamine releases. 156 In the healthy heart, norepinephrine-activated α2ARs act as a negative feedback to inhibit norepinephrine release. 156 Gene deletion of α2AAR (α2A-adrenergic receptor) or α2CAR (α2C-adrenergic receptor), or both of them, in mice leads to elevated norepinephrine levels and worsening cardiac failure. 157,158 The α2BAR is present in VSMCs and regulates vasoconstriction. 159

Muscarinic Receptors

Muscarinic receptors are ubiquitously expressed in human organs and are involved in several pathophysiological processes, ranging from smooth muscle contraction to glandular secretion. 226 As a consequence, the possibility of targeting these receptors for therapeutic purposes has been extensively investigated, including for cardiovascular diseases. There are 5 major subtypes of muscarinic receptor (M1, M2, M3, M4, M5). Among the different subtypes, M1, M3, and M5 signal through Gq, whereas M2 and M4 couple to Gi, 227 supporting their different roles in cardiac physiology (Table). In the heart, the predominant isoform is the M2 receptor, and its fundamental function is to mediate parasympathetic signaling, mainly by inhibiting the heart rate response. 164 In response to acetylcholine, the activated M2 receptor binds Gi leading to a reduction of intracellular cAMP, reduced If current through the HCN (hyperpolarization-activated cyclic nucleotide-gated) channel, 166,167 a decrease in intracellular Ca 2+ , 168 with subsequent negative chronotropic and inotropic effects. Simultaneously, released Gβγ subunits activate the muscarinic-gated potassium channel further promoting the negative chronotropic effects. 228

In patients with HF, M2 muscarinic receptor density is upregulated, whereas the other subtypes are unchanged, 163,164,169,229 and activated M2 receptors may promote inotropic response through myosin light-chain phosphorylation. 230 Functional M3 subtype also seems to play an important role in the heart. 170

Muscarinic receptors were one of the first examples of biased signaling. Indeed, since the early 90s different analogs of acetylcholine have been screened for their ability of selectively activating a limited number of signaling pathways downstream the M1 receptor, as a possible therapy for Alzheimer disease. 161 Recently, the discovery of mutations in both allosteric and orthosteric binding pockets, along with other sites, has aroused a new interest in the therapeutic potential of these receptors. 231,232 In addition, well-known drugs are assuming a new role. An example is given by the pilocarpine—a muscarinic receptor agonist commonly used as cure for glaucoma and dry mouth, which now has been found as a β-arrestin–biased ligand for the M3 receptor. 162 Moreover, β-arrestin itself seems to act as molecular switch at the M1 receptor that coordinates not only its desensitization but also diacylglycerol-dependent signaling ending. 232 Hence, the use of biased agonist at these receptors seems particularly promising.

Endothelin Receptors

Of the 4 ETs (ET 1–4), ET-1 is the major isoform found in the cardiovascular system. Chronic stimulation with ET-1 is associated with adverse effects ranging from myocyte hypertrophy 178 to hypertension 179 and high levels of ET-1 in plasma have been found in both patients and experimental models of HF. 233,234 ET-1 exerts its effects by binding to either the ETAR (ETA receptor) or the ETBR (ETB receptor Table) however ETA seems to be the major player in the heart. In both atrial and ventricular tissue, ETARs couple to Gq promoting IP3 formation and activate MAPK signaling. 235 In atria, ETARs could also lead to inhibition of adenylyl cyclase, likely through Gi coupling. Also, in human vessels have been found different molecules acting as biased ligands, which could be relevant in hypertension. 176,177 Inhibition of ET signaling results in a prolonged survival in experimental HF, 236 although ETR (endothelin receptor) blockade in clinical trials with human HF has not been shown to be beneficial. 237,238

A recent meta-analysis of clinical trials that tested 4 ETR antagonists, bosentan, sitaxentan, macitentan, or ambrisentan, revealed various significant adverse effects of each drug. 239 It is clear that although ETR antagonists confer protective effects on the cardiovascular systems, they also promote various unwanted side effects. The development of drugs that avoid these effects is, therefore, desirable. To this end, the crystal structure of the ETBR bound to bosentan was recently deciphered. 240 This study revealed detailed interactions between the two, which are likely conserved in the closely related ETAR. The hope is that a sounder structural understanding of the relationship between this antagonist and the receptor will enable the rational design of therapeutically superior alternatives.

Adenosine Receptors

Adenosine is an adenine base purine and exerts its function in a lot of physiological processes, including those occurring in the cardiovascular system. Adenosine action is mediated via GPCRs known as ARs (adenosine receptors). There are 4 subtypes of ARs: A1R (adenosine A1 receptor), A2aR (adenosine A2a receptor), A2bR (adenosine A2b receptor), and A3R (adenosine A3 receptor Table). 241 Although all ARs bind adenosine, each receptor differs in several respects, including expression in various cell types and the transducers and effectors that they couple to. A1Rs and A3Rs transmit their signal mainly through Gi, inhibiting cAMP production, whereas A2Rs couple primarily to Gs. Gβγ subunits released by AR stimulation also play an important role in cell growth and remodeling, which is not surprising because Gβγ signaling has been shown for other GPCRs. 228 A1R interacts with PLC, influencing inositol 1,4,5–triphosphate and Ca 2+ release and indirectly modulating K + and Ca 2+ channels. 163,188

As shown for other GPCRs, also the ARs display biased signaling, like the biased agonist VCP746, which has no effect on heart rate while reducing hypertrophy in rat, 185 or capadenoson—a known A1R partial agonist able to contrast cardiac remodeling in an animal model of HF–has been found acting as a biased ligand for A2BR in both fibroblasts and cardiomyocytes. 186 Another example is given by the inosine, which acts as a biased ligand on the A2aR in a unique way prolonging the adenosine stimulation. 187

In the vasculature, A2R is considered the main subtype involved in adenosine signaling, 188 whereas in the heart, adenosine-induced cardioprotective effects are mainly mediated by A1Rs, whose activation has been shown to protect from I/R injury to counteract several processes associated with HF, like arrhythmogenesis, fibrosis, apoptosis, hypertrophy, and ventricular dysfunction and to promote a positive effect on development of HF. 189,191,192

A1Rs are considered potential therapeutic targets in HF, and several agonists and antagonists have been tested. 242 Different studies have been done in human with A1R antagonists, such as rolofylline and KW-3902 243,244 however, despite improved renal function and a positive effect on HF, various side effects, such as increase in stroke, have diminished the impact of this therapy. 243 In contrast, A1R agonists have been used successfully to control heart rate for treatment of arrhythmias 245 and are safe to use in patients with chronic HF. 246 Nowadays, the possibility of using a partial agonist seems a attractive prospect, 247 as well as the possibility of discovering a biased ligand, thereby activating the receptor avoiding negative effects because of broader spectrum action. However, considering that A1Rs exert their action mainly in the heart and A2R in the vasculature with a potentially different outcome, it will be important to determine whether a biased ligand shows selectivity for a specific pathway activation, as well as for each receptor subtype.

Other GPCRs

Over 200 GPCRs are expressed in the heart (Table). 248 In addition to the receptors discussed above, several others have been identified to have important implications in the development or treatment of cardiovascular disease. For instance, the serotonin 5-HT2b receptor regulates cardiac development and function, and its activation promotes cardiac fibrosis and hypertrophy. 204,249 Antagonists of the histamine H2 receptor improved the cardiac function of patients with chronic HF. 250 Activation of APJ (apelin receptor) by apelin increases cardiac contractility, 251 promotes vasodilation, and enhances cardiac output. 252 The peptide hormone relaxin and its receptors exert antifibrosis and cardioprotective roles, and serelaxin (recombinant human relaxin 2) is under development as treatment for acute HF. 216 Blockade of vasopressin V2 receptors prevents myocardial dysfunction and renal injury in experimental HF. 253 Activation of cardiac sphingosine-1-phosphate receptors has been shown to confer cardioprotective effects. 222 The main effects of these GPCRs on heart and blood vessels are outlined in Figure 3C.


GPCRs play vital roles in the physiological regulation of cardiac function and are major drug targets for the treatment of a wide variety of cardiovascular disease. Advances in our understanding of GPCR structure and function have led to a new wave of drug development that aims to enhance receptor specificity and promote distinct ligand-directed signaling efficacies. For instance, biophysical studies of GPCR structures now allow for in silico docking of chemical compounds and structure-based drug design. One of the major challenges of early GPCR structure studies was the instability of the receptor and the transient existence of the receptor-transducer signaling complexes. Recent advances in identifying various formats of GPCR-targeted antibodies to lock receptors in specific conformational states or in complex with signaling partners, such as Fab (antigen-binding fragment) and nanobodies, as well as advances in electron cryomicroscopy (CryoEM) technology now allow for atomic-resolution characterization of heterogeneous structural ensembles. These technological and methodological advances will continue to provide significant insights into the dynamic features of GPCR structure and function. Elucidating the mechanisms for selective activation of GPCR signaling components by biased agonists may yield new drugs that are able to more precisely enhance desired cardioprotective effects while blocking potential untoward detrimental actions or diminishing off target side effects. As new GPCR ligands and mechanisms of action are discovered, many potential therapeutic targets will become evident that one day may be translated into new therapeutic strategies and medicines.

GPCRs: Gi and Gs - Biology

GPCRs undergo cycles of activation and inactivation. In the inactive state, the heterotrimeric G-protein is composed of tightly associated GDP (guanosine-5&rsquo-diphosphate)-bound G&alpha and G&beta&gamma subunits. Upon ligand binding, GPCRs undergo a conformational change, catalyzing G&alpha to exchange GDP for GTP (guanosine-5&rsquo-triphosphate). Then, GTP-bound G&alpha and G&beta&gamma dissociate from the GPCR and activate downstream signaling effectors. Hydrolysis of G&alpha-GTP to G&alpha-GDP causes the reassociation of the heterotrimeric G-protein with the GPCR.

Heterotrimeric G proteins signal through four classes of G&alpha proteins: Gs/olf, Gi/o, G12/13, and Gq. Gs/olf stimulates adenylyl cyclase (AC) whereas Gi/o inhibits it. G12/13 activates RhoGEFs (Ras homology guanine nucleotide exchange factors). The Gq subfamily contains four types of &alpha-subunits (G&alphaq, G&alpha11, G&alpha14, and G&alpha16) they all stimulate phospholipase C &beta (PLC-&beta) G&alphaq/11 has also been shown to activate p63RhoGEF. While early work focused on G&alpha signaling, G&beta&gamma also activates signal transduction cascades.

In the late 1950s, Sutherland and Rall were the first to characterize how GPCRs activate second messenger cascades. They showed that stimulation of various tissues with epinephrine or glucagon (both GPCR agonists) promoted the production of cyclic adenosine monophosphate ( cAMP) by AC. Mammals express at least nine different isoforms of AC that vary in their pattern of tissue ex pression and regulation.

The production of cAMP by AC can be inhibited as well as stimulated. Gi-coupled GPCRs inhibit AC. Pertussis toxin catalyzes the ADP-ribosylation of Gi, which prevents GPCR coupling and inhibition of AC.

Heterotrimeric G proteins and monomeric Ras GTPases both share the feature of being inactive in the GDP-bound state and active in the GTP-bound state. Guanine nucleotide exchange factors (GEFs) catalyze the exchange of GDP for GTP to generate the active Ras GTPase. Ras GTPase signaling is terminated via GTPase activating proteins (GAPs), which accelerate the intrinsic GTPase activity of Ras family members.

The Ras-related small GTPase protein super family contains the Rho GTPase subfamily. The human Rho GTPase subfamily contains 22 members the most extensively characterized members of this family are RhoA, Rac1, and CDC42 due to their ability to cause striking changes in cell morphology upon activation. Rho GTPases have been implicated in a variety of cellular responses including gene transcription, embryogenesis, and actin cytoskeletal dynamics.

Stimulation of G12/13-coupled GPCRs leads to G &alpha-GTP binding of the RH domain of RhoGEF. This induces a conformational change in RhoGEF, activating it. Activated RhoGEF can then activate the RhoGTPase by promoting the release of bound GDP, which then allows the subsequent binding of GTP.

Most GPCRs that couple to G12/13 also couple to Gq. Gq-coupled GPCRs stimulate PLC-&beta, which catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) to IP3 and diacylglycerol (DAG). IP3 binds IP3 receptors on the endoplasmic reticulum (ER) and induces calcium release. PLC-&beta promotes the termination of Gq-GPCR signaling complexes by stimulating GTP hydrolysis of the GTP-bound Gq.

While PLC-&beta has been thought of as being the canonical Gq effector, evidence from the last decade has shown that Gq-GPCRs are also potent activators of p63RhoGEF. Northern blot analysis and immunohistochemistry suggest that p63RhoGEF is expressed in human heart and brain tissue. Several groups of investigators have shown that p63RhoGEF activates the small GTPase RhoA, but not Rac1 or CDC42.

Astrocytes express GPCRs that signal through all four classes of G&alpha proteins. Astrocyte signaling via three of those classes Gs, Gi, and G12/13-coupled GPCRs is poorly understood. Astrocytic Gq-GPCRs have been the most extensively studied because of the early development of calcium indicator dyes that allow the monitoring of cytoplasmic calcium concentrations in real time.

How do GPCRs work?

The first step in signal transduction is ligand binding. The nature of GPCR ligand-binding sites is best studied by a combination of site-directed mutagenesis, molecular modelling of the receptors and screening of large numbers of potential ligands. Our group curates the largest publicly accessible database of ligand affinities as part of the Psychoactive Drug Screening Program (, while the most comprehensive database of the effects of mutations in GPCRs upon ligand binding can be found at Agonist binding is followed by a change in the conformation of the receptor that may involve disruption of a strong ionic interaction between the third and sixth transmembrane helices (Ballesteros et al., 2001 Shapiro et al., 2002), which facilitates activation of the G-protein heterotrimer. Depending on the type of G protein to which the receptor is coupled, a variety of downstream signalling pathways can be activated (reviewed by Marinissen and Gutkind, 2001 Neves et al., 2002). Signalling is then attenuated (desensitized) by GPCR internalization, which is facilitated by arrestin binding (Ferguson, 2001). Signalling, desensitization and eventual resensitization are regulated by complex interactions of various intracellular domains of the GPCRs with numerous intracellular proteins (Hall and Lefkowitz, 2003 Bockaert et al., 2003).

Although many studies have used β-adrenergic receptors as prototypical GPCRs, it has become increasingly clear that much more can be learned by systematic study of other receptors. Our studies of the serotonin 5-HT2A receptor, for instance, showed that GPCR internalization and desensitization can occur by arrestin-independent pathways (Bhatnagar et al., 2001 Gray et al., 2003) and similar findings have been reported for other GPCRs (Lee et al., 1998). Interactions of GPCRs with other proteins, including cytoskeletal components such as PSD-95 (Hall and Lefkowitz, 2002 Xia et al., 2003), are increasingly being found to be important for regulating the activity, targeting and trafficking of GPCRs.

Course Description

How do we communicate with the outside world? How are our senses of vision, smell, taste and pain controlled at the cellular and molecular levels? What causes medical conditions like allergies, hypertension, depression, obesity and various central nervous system disorders? G-protein coupled receptors (GPCRs) provide a major part of the answer to all of these questions. GPCRs constitute the largest family of cell-surface receptors and in humans are encoded by more than 1,000 genes. GPCRs convert extracellular messages into intracellular responses and are involved in essentially all physiological processes. GPCR dysfunction results in numerous human disorders, and over 50% of all prescription drugs on the market today directly or indirectly target GPCRs.

In this course, we will discuss GPCR signal transduction pathways, GPCR oligomerization and the diseases caused by GPCR dysfunction. We will study the structure and function of rhodopsin, a dim-light photoreceptor and a well-studied GPCR that converts light into electric impulses sent to the brain and leads to vision. We will also discuss how mutations in rhodopsin cause retinal degeneration and congenital night blindness.

This course is one of many Advanced Undergraduate Seminars offered by the Biology Department at MIT. These seminars are tailored for students with an interest in using primary research literature to discuss and learn about current biological research in a highly interactive setting. Many instructors of the Advanced Undergraduate Seminars are postdoctoral scientists with a strong interest in teaching.

Watch the video: G-protein coupled receptors GPCRs (January 2022).