G-Protein–Coupled Receptors in Heart Disease
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Abstract
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 Ca2+ release from endoplasmic reticulum. Increased intracellular Ca2+ 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 endosomes12; the β1AR (β1-adrenergic receptor) on cardiomyocyte nuclear membrane acts to activate adenylyl cyclase13; ET (endothelin) stimulates the nuclei-localized ET receptors to modulate nuclear Ca2+ concentration14; 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 stimulation21 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 recruitment57 (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 receptor66 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.
Cardiomyocyte
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 Ca2+ level or myofilament-Ca2+ sensitivity, such as L-type Ca2+ 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 pathway75 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
Fibroblast
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 molecule102; 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 hypertrophy52 and promote cardiac contractility51,104 and cardiomyocyte survival after ischemic injury,51 whereas the β-arrestin–biased ligand, TRV120067, can improve cardiac function through the alteration of the myofilament-Ca2+ 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
Cardiomyocyte
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 Ca2+ 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.
Fibroblast
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 production131 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 Ca2+ 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
| Effects of Receptor Activation on Different Cell Types | ||||||||
|---|---|---|---|---|---|---|---|---|
| Receptors | Transducers | Known Biased Ligands | Main Functions | Example of Clinical Agents for Cardiovascular Diseases | VSMCs | ECs | Fibroblasts | Cardiomyocytes |
| αARs (α1A, α1B, α1D, α2A, α2B, α2C) | Gαq (α1A, α1B, α1D); Gαi (α2A, α2B, α2C) | Desipramine (α2A)160 | Cardioprotective effect (α1A, α1B, α1D)149,150; inhibit norepinephrine release (α2A, α2C)157,158 | Phenoxybenzamine, doxazosin, terazosin, midodrine, carvedilol, bucindolol, labetalol, indoramin, phentolamine, prazosin, clonidine, methyldopa | Vasoconstriction (α1D, α2B)148 | Regulate EC proliferation, angiogenesis, and vasodilation (α1B)155 | Promote physiological hypertrophy147 and antiapoptosis; increase contractility (α1A, α1B)149,150 | |
| Muscarinic receptors (M1, M2, M3, M4, M5) | Gαq (M1, M3, M5); Gαi (M2, M4) | AF102B (M1)161; pilocarpine (M1, M3)162 | Heart rate reduction163,164; reduce intracellular cAMP and Ca2+; negative inotropic and chronotropic effect (M2)165–169; stress response (M3)170 | Atropine, isoproterenol, forskolin, acetylcholine, carbachol, atropine, cryptenamine; pirenzepine, AF-DX 116, methoctramine, flaxedil, methacholine, gallamine triethiodide, pilocarpine | Reducing vasoconstriction171 | Vasodilatation; intracellular Ca2+ overload (M3); release of NO (M1, M3) 172,173 | Increase proliferation and collagen synthesis (M2)174 | Reduce heart rate; modulate contractility163,165; induce NO production175 |
| ET receptors (ETAR, ETBR) | Gαq/Gαi | BQ-123 (ETAR)176; ICB2 (ETBR)177 | Myocyte hypertrophy178; hypertension176,177,179 | Sitaxentan, ambrisentan, atrasentan, BQ-123, zibotentan (ETAR); BQ-788, A192621 (ETBR); bosentan, macitentan, tezosentan (ETAR, ETBR) | Increase intracellular Ca2+ levels; promote vasoconstriction (ETAR)180 | Promote NO and prostacyclin production181; vasorelaxant effect (ETBR)182 | Increase proliferation183 and collagen synthesis183,184 (ETAR, ETBR) | Increase hypertrophy178 |
| ARs (A1R, A2aR, A2bR, A3R) | Gαi (A1R, A3R); Gαs (A2aR, A2bR) | VCP746 (A1R)185; capadenoson, inosine (A2aR)186,187 | Modulate K+ and Ca2+ channels (A1R)163,188; cardioprotective effect (A2aR, A2bR)189–192 | Caffeine, theophylline, theobromine rolofylline, BG-9928, SLV-320; binodenoson | Modulate cell proliferation and migration and monocyte adhesion (A2bR)193 | Promote NO production (A1R)194; mediate proliferation, apoptosis, and vasodilatation (A2aR, A2bR, A3R)188,195,196 | Reduce cell proliferation and collagen synthesis (A2aR)197 | Contrast hypertrophy, fibrosis, and oxidative stress (A1R)192 |
| Serotonin receptors (5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, 5-HT1F, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT4, 5-HT5A, 5-HT5B, 5-HT6, 5-HT7) | Gαi (5-HT1, 5-HT5); Gαq (5-HT2); Gαs (5-HT4, 5-HT6, 5-HT7) | Lysergic acid diethylamide, ergotamine (5-HT2B)198 | Modulate heart rate (5-HT4)199; vasoconstriction and vasodilation (5-HT1B, 5-HT2A, 5-HT2B, 5-HT4, 5-HT7)199 | Ketanserin | Promote interleukin-6 synthesis (5-HT2A)200 | Promote NO release (5-HT2B)199 | Regulate cytokine production, increase oxidative stress (5-HT2B)201,202 | Differentiation, proliferation, and hypertrophy (5-HT2B)203,204 |
| Histamine receptors (H1, H2, H3, H4) | Gαq (H1); Gαs (H2); Gαi (H3, H4) | Famotidine, ranitidine, tiotidine (H2)205; JNJ7777120, VUF10214 (H4)206 | Vasoconstriction (H1); increase heart rate and vasodilation (H2); decrease norepinephrine release (H3)207,208 | Quinidine | Increase intracellular Ca2+ levels (H1)209 | Promote NO release (H2)210 | Increase calcineurin and promote fibrosis (H2)211 | Induce positive chronotropic and inotropic responses; promote apoptosis (H2)211,212 |
| APJ | Gαi, Gαq | MM07, apelin-17(1–16), [Pyr1]apelin-13213 | Increase cardiac contractility214; vasodilation215 | Inhibit proliferation; promote apoptosis213 | Promote NO release213 | Induce positive inotropy214 | ||
| Relaxin family peptide receptors (RXFP1, RXFP2, RXFP3, RXFP4) | Gαs, Gαi (RXFP1, RXFP2); Gαi (RXFP3, RXFP4) | B7-33, ML290 (RXFP1)216 | Induces positive inotropy and chronotropy; vasodilation; angiogenesis; antifibrotic217 | Serelaxin | Vasodilation (RXFP1)217 | Promote NO release (RXFP1)217 | Inhibit proliferation, differentiation, and collagen synthesis (RXFP1)218 | Antiapoptotic (RXFP1)217 |
| Vasopressin receptors (V1a, V1b, V2) | Gαq (V1a, V1b); Gαs (V2) | MCF14, SR121463 (V2) 66 | Vasoconstriction; promote fibrosis; induce cardiomyopathy (V1a)219 | Conivaptan, mozavaptan, tolvaptan, lixivaptan, satavaptan | Increase intracellular Ca2+ levels; promote vasoconstriction (V1a)219 | Promote cell growth and proliferation (V1a)219 | Modulate βAR responsiveness and cellular metabolism; induce hypertrophy (V1a)219 | |
| Sphingosine 1-phosphate receptors (S1PR1, S1PR2, S1PR3, S1PR4, S1PR5) | Gαi (S1PR1); Gαs, Gαq, Gα12/13 (S1PR2); Gαi, Gαq, Gα12/13 (S1PR3); Gαi, Gα12/13 (S1PR4, S1PR5) | ApoM+ HDL-S1P (S1PR1)220; FTY720 (S1PR3)221 | Cardioprotective effect (S1PR2, S1PR3); promote fibrosis (S1PR1, S1PR3) 222 | Inhibit migration (S1PR2); promote vasoconstriction (S1PR3) 222 | Enhance NO production; promote migration and adherens junction assembly (S1PR1); promote angiogenesis (S1PR3)222 | Increase interleukin-6 generation; promote fibrosis (S1PR1)223; promote proliferation (S1PR3)222 | Decrease myofilament contractility224; required for heart development (S1PR1)225 | |
α2ARs couple to Gi to inhibit adenylyl cyclase, reducing the generation of cAMP and decreasing intracellular Ca2+ 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 Ca2+,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 hypertrophy178 to hypertension179; 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 Ca2+ release and indirectly modulating K+ and Ca2+ 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-3902243,244; 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 arrhythmias245 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.
Conclusions
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.
| αAR | α-adrenergic receptor |
| βAR | β-adrenergic receptor |
| 7TMR | 7-transmembrane receptor |
| A1R | adenosine A1 receptor |
| A2aR | adenosine A2a receptor |
| A2bR | adenosine A2b receptor |
| A3R | adenosine A3 receptor |
| ACE | angiotensin-converting enzyme |
| Ang [1–7] | angiotensin [1–7] |
| Ang II | angiotensin II |
| APJ | apelin receptor |
| AR | adenosine receptor |
| ARB | angiotensin receptor blocker |
| AT1R | angiotensin II type 1 receptor |
| AT2R | Ang II type 2 receptor |
| BAD | BCL2-associated agonist of cell death |
| BLAST-AHF | Biased Ligand of the Angiotensin Receptor Study in Acute Heart Failure |
| C terminus | carboxy-terminal tail |
| CRISPR/Cas9 | clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat–associated 9 |
| EC | endothelial cell |
| ECM | extracellular matrix |
| EGFR | epidermal growth factor receptor |
| eNOS | endothelial NO synthase |
| ERK | extracellular signal-regulated kinase |
| ET | endothelin |
| ETAR | ETA receptor |
| ETBR | ETB receptor |
| ETR | endothelin receptor |
| Fab | antigen-binding fragment |
| Gαi | Gαinhibitory |
| Gαs | Gαstimulatory |
| G protein | guanine nucleotide-binding protein |
| GPCR | G-protein–coupled receptor |
| GRK | G-protein–coupled receptor kinase |
| HF | heart failure |
| ICL | intracellular loop |
| MAPK | mitogen-activated protein kinase |
| MLCK | myosin light-chain kinase |
| MMP | matrix metalloproteinase |
| MNK1 | serine/threonine kinase 1 |
| NF-κB | nuclear factor-κB |
| PDE4 | phosphodiesterase 4 |
| PI3K | phosphoinositide 3-kinase |
| PKA | protein kinase A |
| PKC | protein kinase C |
| PLC | phospholipase C |
| TGF-β | transforming growth factor-β |
| TM | transmembrane domain |
| TNF-α | tumor necrosis factor-α |
| VSMC | vascular smooth muscle cell |
| WT | wild type |
Sources of Funding
This work was supported, in part, by US National Institutes of Health grants R01 HL056687 and P01 HL075443 to H.A. Rockman.
Disclosures
H.A. Rockman is a cofounder of Trevena, Inc—a company that discovers and develops novel GPCR (G-protein–coupled receptor)-targeted therapeutics. The other authors report no conflicts.
Footnotes
References
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