|Year : 2019 | Volume
| Issue : 2 | Page : 68-75
G protein-coupled receptor signaling in cardiovascular system: Specificity versus diversity
Shyamal K Goswami
School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
|Date of Submission||14-Jun-2019|
|Date of Decision||24-Jun-2019|
|Date of Acceptance||27-Jun-2019|
|Date of Web Publication||19-Aug-2019|
Prof. Shyamal K Goswami
School of Life Sciences, Jawaharlal Nehru University, New Delhi - 110 067
Source of Support: None, Conflict of Interest: None
In metazoan organisms, communication of the constituent cells to its exterior is an essential component of tissue homeostasis and organ function. A plethora of growth factors, cytokines, hormones, regulatory small molecules, etc., interact with the cells surface receptors to initiate the signaling process that is transduced to the cell interior, regulating its functions. Over the years, thousands of such receptors have been identified and characterized. This number has substantially gone up in the postgenome era. Although the mechanisms of signal transduction by cell surface receptors is of immense interest for both clinicians and basic biologists, certain group of receptors have drawn equal attention of both the communities. One such group is the G protein-coupled receptors (GPCRs). Over the past half a century, this group of receptors has been extensively investigated, and a volume of information regarding their complexity as well as diversities has been revealed. Another interesting aspect of the GPCR study is their predominant roles in drug discovery and development. A substantial number of commonly used drugs are targeted toward the GPCR family, and several more are expected to be coming to the market in near future. Taking into consideration of the importance of these receptors, the following review summarizes certain fundamental aspects of its signaling mechanisms. Considering the vast information available on GPCRs and their importance in human health and diseases, following review provides a broad outline on the mechanisms of their functional diversity.
Keywords: Cardiovascular, cell signaling, G protein-coupled receptor, G proteins
|How to cite this article:|
Goswami SK. G protein-coupled receptor signaling in cardiovascular system: Specificity versus diversity. J Pract Cardiovasc Sci 2019;5:68-75
|How to cite this URL:|
Goswami SK. G protein-coupled receptor signaling in cardiovascular system: Specificity versus diversity. J Pract Cardiovasc Sci [serial online] 2019 [cited 2019 Dec 10];5:68-75. Available from: http://www.j-pcs.org/text.asp?2019/5/2/68/264630
| Introduction|| |
In a multicellular organism, functions of each cell are regulated by two modules: the intrinsic cellular constituents (as in liver cells versus nerve cells) and the external cues (like cytokines for immune cells versus neurotransmitters for the nerve cells). Each mammalian cell is studded with a large number of receptors, which span across the cell membrane, outwardly protruding the extracellular domain while inwardly extending into the cell interior. Numerous regulatory molecules (called ligands) bind to those receptors and activate a process transmitting the stimulatory signal into the cell interior through a series of kinases/phosphatases and small molecules called second messengers. A large number of growth factors, cytokines, and peptide hormones transmit their signals through this mechanism. Since the structure of the receptors and their ligands are highly specific, their interactions and subsequent signaling processes are also highly selective. Such signaling mechanism primarily involves activation/inactivation of mediator molecules through conformational changes, generation of second messengers, and posttranslational modifications (like phosphorylation/dephosphorylation). Recent studies have highlighted oxidative modification of cysteine thiols as another mode of signal transduction called redox signalling. Studies over the years have suggested that the structures of these receptors and the biochemical mechanisms they use for the transmission of signals are conserved in evolution. Accordingly, these receptors are classified as enzyme-linked receptors (e.g., tyrosine kinases), G protein-coupled receptors (GPCRs) (e.g., insulin receptor and angiotensin receptor), and ion channel-linked receptors (e.g., adenosine 5'-triphosphate-gated channels). Quite often, it is observed that despite a large number of receptors having highly conserved structures and common signal intermediates, their signaling mechanisms are highly selective (as it is expected for maintaining the fidelity of the biological processes). One such family is GPCRs, and in the present review, I will explain how a diverse group of GPCRs use a common mechanism of signal transduction and still maintain the selectivity of their effects.
| G Protein-Coupled Receptor Superfamily|| |
GPCR constitute a family that is characterized by α-helical domains that pass through the cell membrane seven times (for this unique structural feature, they are also called seven-transmembrane domain receptors). They are one of the largest family of cell surface receptors found in mammals. In airway smooth muscle cells, a large number of GPCRs are expressed, creating a highly complex receptor system. RNA analysis has shown the presence of 434 GPCRs transcripts (including splice variants) in those cells. Ligands that activate them are as diverse as light-sensitive compounds, organic odorants, amines, peptides, proteins, lipids, nucleotides, etc. They are also the targets of ~40% of all drugs developed by the pharmaceutical industries until date. Further, majority of those drugs are targeted to only a small subset of the receptors whose functions are well understood. Therefore, it is expected that in coming years, a large repertoire of drugs will be developed whose targets will be a wide spectrum of human GPCRs regulating various physiological processes. Understandably, research in GPCR signaling is very prevalent, and till date, nine Nobel prizes have been awarded in this field. Most recent one was awarded to Robert Lefkowitz and Brian Kobilka (2012, Chemistry) for studying their structure and function. [Table 1] summarizes the various physiological functions attributed to GPCRs.
The present day knowledge suggests that the number of GPCR in mammals is very high, and till date, ~ 800 human genes (≈4% of the entire protein-coding genes) code for GPCRs. As expected, functions of many of these GPCRS have not yet been characterized. Despite having no major sequence homology among the GPCRs, they have a common structure (seven-transmembrane domain) and mechanisms (G protein coupled) of signal transduction. Considering their importance in human biology, a number of classification schemes have been proposed to categorize them. Some systems group the receptors based on their ligands, while others have used their physiological and structural features for the criteria of classification. One of the most frequently used classification system divides them in groups based on their sequence homology as well as the prototype ligands (thus functionally, similar receptors are grouped together). This classification system covers both vertebrates and invertebrate receptors.,
According to this classification system, the following are the GPCR groups*
- Class A: Rhodopsin-like
- Class B: Secretin receptor family
- Class C: Metabotropic glutamate/pheromone
- Class D: Fungal mating pheromone receptors
- Class E: Cyclic AMP receptors
- Class F: Frizzled/Smoothened
- Class O (Other receptor) [Taste 2].
*D and E do not exist in human.
GPCRs are coupled to “heterotrimeric G proteins” consisting of three subunits named Gα, Gβ, and Gγ in a complex attached to the cytoplasmic side of plasma membrane. In the inactive form, the Gα subunit remains bound to guanosine diphosphate (GDP) (or in certain instances, no nucleotide). Once ligand binds the GPCR, the complex is activated and guanosine triphosphate (GTP) replaces GDP. The receptor, Gα-GTP complex, and Gβγ assembly then dissociate from one another, generating three independent modules transmitting the signals to the downstream effectors. There are some instances where the Gα-GTP-Gβγ assembly does not dissociate but rather undergoes conformational change, initiating signals. Furthermore, there are instances where the Gβγ complex moves into the cytoplasm or to membranes of other organelles. In humans, there are twenty-one Gα proteins encoded by sixteen genes, six Gβ proteins encoded by five genes, and twelve G03B3 subunits. These repertoires of G proteins suggest the diversity of GPCR signaling. However, considering the large number of GPCRs and much fewer number of G proteins, it is expected that each particular type of Gαβγ complex must be interacting with many different receptors. Furthermore, depending on the agonist (ligand), some receptors can activate multiple signaling pathways.,
| Diversity of G Protein-Coupled Receptor Signaling|| |
One of the major sources of diversity of GPCR signaling is the type of Gα subunit the receptor is coupled to. Depending on the signals they generate, Gα proteins are of four different types, namely Gαs, Gαi/o, Gαq/11, and Gα12/13., The downstream targets of both the Gαs and Gαi/o signaling are adenylate cyclases that generate cyclic AMP. However, while the Gα subunits stimulate the enzyme, the Gαi/o inhibits it. Accordingly, GPCRs coupled to Gαs and Gαi/o will counteract the effects of each other and thus calibrate the level of cAMP in the cytosol, which in turn will regulate the activity of its downstream targets. 26RFa and 43RFa are neuropeptides of RFamide family (as they have Arg-Phe-amide at the end) signaling through the GPCR 103. They are involved in regulating physiological processes such as reproductive and eating behavior and pain modulation. In human pancreatic islets, while both prevent cell death induced by cytokines and glucolipotoxicity, 43RFa promotes glucose-induced insulin secretion but 26RFa inhibits it through Gαs and Gαi/o pathways, respectively. The downstream mediators of Gαq/11 pathway is phospholipase C (PLC)-β, which catalyzes the conversion of phosphatidylinositol 4,5-biphosphate (PIP2), a membrane-associated lipid, into inositol 1, 4, 5 trisphosphate (IP3) and diacylglycerol (DAG). IP3 facilitates Ca2+ release from the endoplasmic reticulum while DAG activates protein kinase C (PKC), a serine/threonine kinase. Free fatty acid receptor 2 (FFAR2) is a short-chain fatty acid-sensing GPCR expressing in pancreatic β-cells. Acetate, its endogenous ligand, enhances glucose-induced insulin secretion. However, other FFAR2-specific agonists either increase or inhibit insulin secretion by signaling through Gαq/11 or Gαi/o, respectively. Thus, depending on the ligand, FFAR2 signaling might occur through divergent G protein-coupled pathways. The downstream targets of Gα12/13 are Rho guanyl nucleotide exchange factors which on binding to Gα12/13 activates cytosolic small GTPase Rho.
The angiotensin peptides (Ang I-IV) are derived from the cleavage of the precursor peptide angiotensinogen by proteolytic enzymes rennin, angiotensin I-converting enzyme, etc., Among various angiotensins, Ang II is better studied, and it plays a major role in the maintaining the blood pressure and fluid/electrolyte balance. Two well-studied Angiotensin receptors, AT1 and AT2, are of GPCR family. Both the receptors are coupled to multiple G proteins. The AT1 receptor has been implicated in pathological conditions such as hypertension, heart failure, cardiac remodeling, and fibrosis metabolic diseases. Systematic analyses of receptor signaling have shown that it induces vasoconstriction and cardiac hypertrophy through Gq, cell death through G12/13, and nitric oxide synthesis through Gi. Although the AT2 receptor has all the characteristic features of a GPCR, it does not show the classic features of GPCR signaling., In some instances, the AT2 receptor signal counter acts that by the AT1 receptor. This is an example where in different cellular and physiological contexts, the same receptor and ligand can use multiple G proteins to mediate diverse functions. Such ligands which initiate differential signaling from the same receptor (in same or different tissues) are called biased ligands. Details of biased signaling are further discussed below.
On activation by the ligand, GPCRs dissociate Gαβγ heterotrimer into Gα and Gβγ. Earlier, Gα was believed to be the primary signal initiator and Gβγ was considered as passive component of the signaling system. Later, it has emerged that Gβγ proteins also mediate signals., In human, there are six Gβ and twelve Gγ proteins, creating a large repertoire of Gβγ assembly. Taking into consideration the diversity Gα subunits, the possible combinations of heterotrimeric G protein complexes (comprising of α, β and γ subunits) are quite large with tissue-specific functions. Among the targets of Gβγ complex is cardiac muscarinic-gated inwardly rectifying K+ channel, voltage-dependent Ca2+ channels, certain isoforms of adenylate cyclases, PLC (cleaves PIP2 into the second messengers DAG and inositol 1, 4, 5-triphosphate [IP3]), certain isoforms of phosphoinositide 3 Kinases (PI3Kinases), and mitogen-activated protein kinases (MAPK). Considering such large repertoire of downstream targets, the role of Gβγ in GPCR signaling appears to be much wider than once thought. Recent evidences suggest that on receptor activation, Gβγ dimers can even move from the plasma membrane to other subcellular locations, further diversifying the signals. The kinetic of GPCR signaling also depends on the rate at which the Gα-GTP complex hydrolyzes GTP, yielding the resting form Gα-GDP. Although GTP hydrolysis is done by the Gα protein itself, it can be further facilitated by GTPase acceleratory proteins (GAPs) and regulators of G protein signaling. Some of the GAP proteins are the downstream effectors of GPCR signaling which directly regulate the speed of signaling by its upstream receptor.
| Role of G Protein-Coupled Receptor Kinases and B-Arrestin in Terminating G Protein-Coupled Receptor Signaling|| |
No biological system remains in the perpetually activated state (except under certain disease condition like cancer), and therefore, stimulatory signals are to be terminated so that the second messengers and their target proteins are restored to their basal levels. Modes of termination of GPCR signaling include the removal of the ligand from the receptor and its phosphorylation by GPCR kinases (GRKs). Phosphorylated receptors are inactive in transmitting signals and they are further inactivated by binding to arrestin proteins present in the plasma membrane. The arrestin-receptor complex is then endocytosed to the cell interior. Once it is in the cytosol, the receptor can be dephosphorylated and recycled back to the cell surface in an active form or might as well be degraded in the lysosome. The above mechanisms play an important role in β-adrenergic receptor distribution in heart muscle of normal, elderly, and those with heart failure. Besides this canonical role of GRK in GPCR signaling, other roles of GRK in cell signaling and diseases have also emerged over the years. In human, there are seven GRKs, that is GRK 1–7, which share common structural and functional characteristics. Based on their amino acid sequences and tissue distribution, they are further divided into three subfamilies, namely (1) Rhodopsin kinases (GRKs 1 and 7); (2) β-adrenergic receptor kinases (GRKs 2 and 3); and (3) the GRK4 subfamily that includes GRK 4, 5, and 6. Rhodopsin kinase expresses in retina; GRK4 in testes; and the other GRKs are largely ubiquitous, albeit with certain degree of tissue preferences. In human heart, GRKs 2, 3, and 5 are expressed in higher levels and play critical roles in cardiovascular pathophysiology.
| G Protein Coupled Receptor Signaling in Cardiovascular System|| |
Like any other organ, the regulation of cardiovascular system is also complex under both normal and pathological conditions. Various cell types in the cardiovascular system, namely myocytes, fibroblasts, endothelial, and smooth muscle cells are studded with an array of cell surface receptors that transmit signals generated by the extracellular stimuli. A variety of GPCRs have been associated with almost all major regulatory events in the cardiovascular system, namely myocardial contraction, arterial resistance, renal function, cardiac hypertrophy, and heart failure. GPCRs involved in cardiovascular function include AT1 (angiotensin II), ET1B (endothelin-1), α-adrenergic (epinephrine), β-adrenergic (norepinephrine), APJ (apelin), and CRH-R2 (urocortin) receptors. Furthermore, several other orphan receptors (for which ligands are not known yet) have been attributed to cardiovascular function. [Table 2] summarizes those receptors and their functions.
|Table 2: Various G protein-coupled receptors in the cardiovascular system and their functions|
Click here to view
The effects of norepinephrine and epinephrine released from the sympathetic nervous system are mediated through three α1-adrenergic-(α1A/B/D), three α2-adrenergic-(α2A/B/C), and three β-adrenergic (β1/2/3) receptors. β1 and β2 receptors activate Gαs proteins (stimulatory G proteins) which initiates the generation of cyclic AMP which in turn activates protein kinase A. Interestingly, on phosphorylation by PKA, the β2 receptor switches its signaling from Gs to Gi/o that stimulates apoptosis. The α1-adrenoceptors in human heart are fewer in number, and they play a major role in cardiac hypertrophy and remodeling. They signal through the Gq/11, activating PLCβ-IP3 and 2-diacyl glycerol pathways. Although Type 1 Angiotensin II receptor (AT1) is generally Gq/11 coupled, depending on cell types, it also can couple to Gi/o or Gs proteins. It is primarily expressed in the cardiac fibroblasts and regulates cardiac hypertrophy, inflammation, fibrosis, and other responses often associated to adverse cardiac remodeling. In humans, there are four types of adenosine receptors of which A1, A2A receptors regulate myocardial oxygen consumption and coronary blood flow (They also have important functions in brain while two other receptors, i.e., A2B and A3 are involved in immune responses.). Activation of A1 receptor through Gi/o causes bradycardia, and this pathway is used for the therapeutic intervention against certain types of supraventricular arrhythmias with adenosine. Apelin, a group of endogenous peptides (apelin-36,-17, −13, and −12), is derived from a 77-amino acid prepropeptide by proteolytic cleavage. High level of apelin mRNA and the matured apelin-17 has been reported in numerous tissues including heart. Its cognate receptor is APJ which belongs to the GPCR family. Cardiac apelin-APJ system has a positive inotropic effect; it lowers arterial blood pressure, induces vasodilation, improves cardiac output, and provides cardioprotection under myocardial infarction. In patients with coronary artery disease, serum apelin-12 levels is reduced. Large scale data analysis has shown that serum apelin is a protective marker against the progression of coronary artery diseases. Urocortins (Ucn) 1–3 are another group of peptides (corticotropin-releasing hormone family) having effects on the cardiovascular system wherein it mediates its effect through the CRH-R2 receptor, a member of the GPCR family. Ucn have vasodilatatory and inotropic effects, increase cardiac output, and have cardioprotective effects in patients with heart failure, hypertension, and ischemic heart disease. Due to the significant role of Ucn in cardiovascular pathobiology, clinical trials for potential diagnostic and therapeutic use of Ucn in cardiovascular diseases are being explored.
Taken together, numerous GPCRs are expressed on cardiac myocytes, vascular smooth muscle cells, fibroblasts, endothelial cells regulating vascular tone, heart rate and contractile strength, metabolism, etc. Subsequent to the activation of these receptors by specific ligands, downstream effector molecules such as adenylate cyclases, phospholipases, and certain ion-channels are activated which in turn activate certain second messengers. These second messengers then turn on a plethora of signaling kinases which phosphorylates their target proteins, regulating their function. These pathways also regulate the activity of various phosphatases which dephosphorylates specific targets, attenuating the stimulatory signals. Aberrant signaling by these receptors leads to dysregulation of cell function followed by the diseases such as cardiac hypertrophy, atherosclerosis, and hypertension.
| Protein Kinases in G Protein-Coupled Receptor Signaling|| |
Protein kinases play critical roles in mediating various GPCR signals in the cardiovascular system. Among various protein kinases studied till date, protein kinase A, G, and C are well investigated for their roles in GPCR signaling. Protein kinase A, a cyclic AMP dependent, mediates the adrenergic signaling while protein kinase G, a cyclic GMP-dependent kinase, is the mediator of nitric oxide signaling., Both protein kinase A and G are serine/threonine kinases. Another serine/threonine kinase, namely PKC has roles in cardiovascular biology. PKC has several isoforms. While some are calcium dependent and activated by of DAG and phorbol esters (PKC-α, PKC-β1, PKC-β2, and PKC-γ), several others are calcium independent but require DAG (PKC-δ, PKC-ε, PKC-η, and PKC-θ). A third family are atypical (PKC-ι, PKC-ζ) which are not activated by either calcium or DAG. PKCα is involved in GPCR signaling in normal hearts while PKC ε is important in ischemic preconditioning of the myocardium.
| Noncanonical Signaling by Gβγ , G Protein-Coupled Receptor Kinases, and B-Arrestin|| |
As described above, classical GPCR signaling involves (a) binding of the ligand to the receptor, (b) dissociation of the heterotrimeric G protein (αβγ) into α or βγ, and (c) the interaction of the downstream effectors with the dissociated G protein subunits followed by the transmission of signals. Once GPCRs are activated, the signal is terminated by the phosphorylation of the receptors by GRK, binding of β-arrestins to it, its internalization, dephosphorylation, and recycling. Studies done in early nineties, the primary mediator of the GPCR signaling was presumed to be the Gα that is the classical mode. However, over the years, it has now become apparent that the other constituents of the GPCR viz., Gaβγ, GRK and even β-arrestins play critical roles in the process.
In cardiac myocytes, upon stimulation of endothelin receptor, the Gβγ subunit induces the hydrolysis of phosphatidylinositol 4-phosphate by the PLCε in the Golgi and this pathway is involved in the hypertrophic response. In heart and brain, GPCR mediated inhibitory neurotransmission involves the activation of G protein-gated K(+) (GIRK) channels. Gβγ binds to the cytosolic domain of GIRK and mediates its activation. Signaling by the Gβγ subunit plays an important role in heart failure. In heart failure patients, cytosolic level of GRK2 is elevated and the Gβγ subunit recruits it to the stimulated β-adrenergic receptors resulting in its persistence desensitization and downregulation.
The classical function of GRKs is to regulate the duration and the strength of the GPCR signaling through its phosphorylation and internalization. In addition, recent studies have shown various other functions of GRKs. There are instances GRKs also phosphorylates non-GPCR substrates and perform several phosphorylation-independent regulatory functions. GRK2 is the most abundant among the three GRKs (the other two are GRK 3 and 5) in the heart and its level/activity increases in failing human hearts. It regulates diverse biological events including inflammation, insulin signaling, cell migration, vascular function etc., through the phosphorylation and interactions with various noncanonical substrates like tubulin, synucleins, histone deacetylase, MAPK, Raf kinase inhibitor protein, PI3Kinase etc. Experimental evidences also suggest that it also desensitizes α and β adrenergic, angiotensin, cholinergic muscarinic, endothelin receptors and other GPCRs independent of its phosphorylation function., GRK2 activity is controlled by its phosphorylation at multiple sites by kinases like PKC and c-Src. Due to its hugely complex role in cell functions, exhaustive research have been undertaken on GRK2 in the past two decades and its role in cardiovascular, immune, neurological disorders and in cancer has been established and it is now being considered as a therapeutic target. In experimental mice, following myocardial infarction and heart failure, inhibition of GRK2 by paroxetine improves left ventricular structure-function. Like in the case of GRK2, the expression of GRK5 is also elevated in patients with cardiovascular disorders. Interestingly, it has been demonstrated that subsequent to the activation of Gαq-coupled signaling, GRK5 moves to the nucleus and phosphorylates histone deacetylase-5 kinase inducing the expression of the transcription factor MEF2, that upregulates the expression of the markers of hypertrophy. GRK5 has also been attributed to other noncanonical gene regulatory functions. Unlike in the case of GRK2 and GRK5, the noncanonical role of GRK3, if any, is not understood as yet.
| B-Arrestins and Biased Signaling by G Protein Coupled Receptor|| |
Like the GRKs, β-arrestins are also involved in the desensitization and internalization of phosphorylated GPCRs. Out of four β-arrestins, β-arrestin 1 and 2 are ubiquitously expressed including in heart. In the canonical pathway, once the receptor is stimulated, it is phosphorylated by the GRK (or protein kinase A and C), followed by its binding to β-arrestins, which takes it to the clathrin coated pits. Thereafter, either it is dephosphorylated and recycled or degraded. However, contrary to the earlier believe that this is how the GPCR signaling ends, in the past twenty years, it has been established that β-arrestin also forms a multi-protein signaling complex where the desensitized receptor also participates. These complexes initiate a signaling process that is distinct from the conventional GPCR signaling per se. Subsequent to the discovery of such independent signaling by the β-arrestin-receptor assembly (called “receptorsome”), a concept of “Pluridimensionality of GPCR Signaling” has emerged. It refers to the concept that GPCRs might diversify the signals via multiple G proteins and non-G protein mediators by adopting multiple conformation having different active states (complexes) in different cellular locations. Their interactions with β-arrestin diversify the signal specificity through the interactions with various protein and lipid kinases, phosphatases, small G proteins, and their regulators. It is now hypothesized that different ligands might differentially alter the conformational state of the receptors. Such diversity of signaling by different ligands for the same receptor is termed as “ligand bias”. Such biased signaling has been shown for several endogenous ligands including the Angiotensin II type 1 receptor which is involved in the development of hypertension. Angiotensin peptide (1–7) lacking the C-terminal phenylalanine residue has vasodilatory and cardioprotective effects, but it does not activate G proteins. It is thus a competitive antagonist for the classical Gαi and Gαq pathways induced by AngII. It has been observed that S-nitrosylation of a cysteine residue β-arrestin 1/2 initiates biased signaling through GPCRs by selectively inhibiting β-arrestin-mediated signal transduction. Such β-arrestin S-nitrosylation induces inflammation, aging, and heart failure. Such evidence of “ligand bias” by the nature has encouraged the pharmacologists to develop synthetic ligands that might regulate the signals differently from the natural ligands, suppressing the detrimental pathways and boosting the beneficial pathways. Such signal divergence by various ligands has a tremendous therapeutic potential. A collective representation of various aspects of GPCR signaling is summarized in [Figure 1].
|Figure 1: A schematic representation of the various stages of G protein-coupled receptor signaling as described in the text. Various constituents of the signaling system are marked using standard annotations. Arrows mark stepwise activation and inactivation of the signaling system. Broken line means alternative ways of transmitting the signal downstream.|
Click here to view
| Concluding Remarks|| |
Past two decades have seen a paradigm shift in approaches toward the therapeutic intervention against cardiac diseases. While on the one hand, a hugely diverse world of GPCRs in human biology has emerged; on the other hand, a myriad of canonical and noncanonical mediators of their signaling have also been revealed. Attempts are now being made for modulating GPCR signaling at all levels from receptor activation to the downstream events. Researchers are tirelessly working for identifying novel small molecule modulators of GRKs and β-arrestins to ensure boosting the beneficial pathways and inhibiting the detrimental one. Furthermore, such knowledge of GPCR signaling in conjunction with modern tools of metabolomics, proteomics, and transcriptomics further enhances our quest for newer and newer therapeutic tools such as microRNAs, epigenetic regulators, RNA aptamers, and gene editors to ameliorate various cardiovascular diseases.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Milligan G, Ward RJ, Marsango S. GPCR homo-oligomerization. Curr Opin Cell Biol 2019;57:40-7.
Einstein R, Jordan H, Zhou W, Brenner M, Moses EG, Liggett SB. Alternative splicing of the G protein-coupled receptor superfamily in human airway smooth muscle diversifies the complement of receptors. Proc Natl Acad Sci U S A 2008;105:5230-5.
Muratspahić E, Freissmuth M, Gruber CW. Nature-derived peptides: A growing niche for GPCR ligand discovery. Trends Pharmacol Sci 2019;40:309-26.
Sloop KW, Emmerson PJ, Statnick MA, Willard FS. The current state of GPCR-based drug discovery to treat metabolic disease. Br J Pharmacol 2018;175:4060-71.
Ayoub MA. Small molecules targeting heterotrimeric G proteins. Eur J Pharmacol 2018;826:169-78.
Lv X, Liu J, Shi Q, Tan Q, Wu D, Skinner JJ, et al. In vitro
expression and analysis of the 826 human G protein-coupled receptors. Protein Cell 2016;7:325-37.
Fredriksson R, Lagerström MC, Lundin LG, Schiöth HB. The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol 2003;63:1256-72.
Isberg V, de Graaf C, Bortolato A, Cherezov V, Katritch V, Marshall FH, et al.
Generic GPCR residue numbers – Aligning topology maps while minding the gaps. Trends Pharmacol Sci 2015;36:22-31.
Xiao X, Wang P, Chou KC. GPCR-2L: Predicting G protein-coupled receptors and their types by hybridizing two different modes of pseudo amino acid compositions. Mol Biosyst 2011;7:911-9.
Wang W, Qiao Y, Li Z. New insights into modes of GPCR activation. Trends Pharmacol Sci 2018;39:367-86.
Eichel K, von Zastrow M. Subcellular organization of GPCR signaling. Trends Pharmacol Sci 2018;39:200-8.
Milligan G, Kostenis E. Heterotrimeric G-proteins: A short history. Br J Pharmacol 2006;147 Suppl 1:S46-55.
Godinho RO, Duarte T, Pacini ES. New perspectives in signaling mediated by receptors coupled to stimulatory G protein: The emerging significance of cAMP efflux and extracellular cAMP-adenosine pathway. Front Pharmacol 2015;6:58.
Kamato D, Thach L, Bernard R, Chan V, Zheng W, Kaur H, et al.
Structure, function, pharmacology, and therapeutic potential of the G protein, gα/q, 11. Front Cardiovasc Med 2015;2:14.
Granata R, Settanni F, Trovato L, Gallo D, Gesmundo I, Nano R, et al.
RFamide peptides 43RFa and 26RFa both promote survival of pancreatic β-cells and human pancreatic islets but exert opposite effects on insulin secretion. Diabetes 2014;63:2380-93.
Priyadarshini M, Villa SR, Fuller M, Wicksteed B, Mackay CR, Alquier T, et al.
An acetate-specific GPCR, FFAR2, regulates insulin secretion. Mol Endocrinol 2015;29:1055-66.
Yuan B, Cui J, Wang W, Deng K. Gα12/13 signaling promotes cervical cancer invasion through the RhoA/ROCK-JNK signaling axis. Biochem Biophys Res Commun 2016;473:1240-6.
Tóth AD, Turu G, Hunyady L, Balla A. Novel mechanisms of G-protein-coupled receptors functions: AT1 angiotensin receptor acts as a signaling hub and focal point of receptor cross-talk. Best Pract Res Clin Endocrinol Metab 2018;32:69-82.
Porrello ER, Delbridge LM, Thomas WG. The angiotensin II type 2 (AT2) receptor: An enigmatic seven transmembrane receptor. Front Biosci (Landmark Ed) 2009;14:958-72.
Matavelli LC, Siragy HM. AT2 receptor activities and pathophysiological implications. J Cardiovasc Pharmacol 2015;65:226-32.
Khan SM, Sleno R, Gora S, Zylbergold P, Laverdure JP, Labbé JC, et al.
The expanding roles of gβγ subunits in G protein-coupled receptor signaling and drug action. Pharmacol Rev 2013;65:545-77.
Senarath K, Kankanamge D, Samaradivakara S, Ratnayake K, Tennakoon M, Karunarathne A. Regulation of G protein βγ signaling. Int Rev Cell Mol Biol 2018;339:133-91.
Yim YY, McDonald WH, Hyde K, Cruz-Rodríguez O, Tesmer JJ, Hamm HE. Quantitative multiple-reaction monitoring proteomic analysis of gβ and gγ subunits in C57Bl6/J brain synaptosomes. Biochemistry 2017;56:5405-16.
Klayman LM, Wedegaertner PB. Inducible inhibition of gβγ reveals localization-dependent functions at the plasma membrane and Golgi. J Biol Chem 2017;292:1773-84.
He W, Cowan CW, Wensel TG. RGS9, a GTPase accelerator for phototransduction. Neuron 1998;20:95-102.
Bansal G, Druey KM, Xie Z. R4 RGS proteins: Regulation of G-protein signaling and beyond. Pharmacol Ther 2007;116:473-95.
van Gastel J, Hendrickx JO, Leysen H, Santos-Otte P, Luttrell LM, Martin B, et al.
B-arrestin based receptor signaling paradigms: Potential therapeutic targets for complex age-related disorders. Front Pharmacol 2018;9:1369.
Belmonte SL, Blaxall BC. G protein coupled receptor kinases as therapeutic targets in cardiovascular disease. Circ Res 2011;109:309-19.
Capote LA, Mendez Perez R, Lymperopoulos A. GPCR signaling and cardiac function. Eur J Pharmacol 2015;763:143-8.
de Lucia C, Eguchi A, Koch WJ. New insights in cardiac β-adrenergic signaling during heart failure and aging. Front Pharmacol 2018;9:904.
Endoh M. Cardiac α1-adrenoceptors and inotropy: Myofilament Ca2+ sensitivity, intracellular Ca2+ mobilization, signaling pathway, and pathophysiological relevance. Circ Res 2016;119:587-90.
Bahreyni A, Avan A, Shabani M, Ryzhikov M, Fiuji H, Soleimanpour S, et al.
Therapeutic potential of A2 adenosine receptor pharmacological regulators in the treatment of cardiovascular diseases, recent progress, and prospective. J Cell Physiol 2019;234:1295-9.
Wysocka MB, Pietraszek-Gremplewicz K, Nowak D. The role of apelin in cardiovascular diseases, obesity and cancer. Front Physiol 2018;9:557.
Opatrilova R, Caprnda M, Kubatka P, Valentova V, Uramova S, Nosal V, et al.
Adipokines in neurovascular diseases. Biomed Pharmacother 2018;98:424-32.
Walczewska J, Dzieza-Grudnik A, Siga O, Grodzicki T. The role of urocortins in the cardiovascular system. J Physiol Pharmacol 2014;65:753-66.
Chatzaki E, Kefala N, Drosos I, Lalidou F, Baritaki S. Do urocortins have a role in treating cardiovascular disease? Drug Discov Today 2019;24:279-84.
Calebiro D, Koszegi Z. The subcellular dynamics of GPCR signaling. Mol Cell Endocrinol 2019;483:24-30.
Boularan C, Gales C. Cardiac cAMP: Production, hydrolysis, modulation and detection. Front Pharmacol 2015;6:203.
Vaniotis G, Glazkova I, Merlen C, Smith C, Villeneuve LR, Chatenet D, et al.
Regulation of cardiac nitric oxide signaling by nuclear β-adrenergic and endothelin receptors. J Mol Cell Cardiol 2013;62:58-68.
Marrocco V, Bogomolovas J, Ehler E, Dos Remedios CG, Yu J, Gao C, et al.
PKC and PKN in heart disease. J Mol Cell Cardiol 2019;128:212-26.
Malik S, deRubio RG, Trembley M, Irannejad R, Wedegaertner PB, Smrcka AV. G protein βγ subunits regulate cardiomyocyte hypertrophy through a perinuclear Golgi phosphatidylinositol 4-phosphate hydrolysis pathway. Mol Biol Cell 2015;26:1188-98.
Dascal N, Kahanovitch U. The roles of gβγ and gα in gating and regulation of GIRK channels. Int Rev Neurobiol 2015;123:27-85.
Casey LM, Pistner AR, Belmonte SL, Migdalovich D, Stolpnik O, Nwakanma FE, et al.
Small molecule disruption of G beta gamma signaling inhibits the progression of heart failure. Circ Res 2010;107:532-9.
Hullmann J, Traynham CJ, Coleman RC, Koch WJ. The expanding GRK interactome: Implications in cardiovascular disease and potential for therapeutic development. Pharmacol Res 2016;110:52-64.
Evron T, Daigle TL, Caron MG. GRK2: Multiple roles beyond G protein-coupled receptor desensitization. Trends Pharmacol Sci 2012;33:154-64.
Schumacher SM, Koch WJ. Noncanonical roles of G protein-coupled receptor kinases in cardiovascular signaling. J Cardiovasc Pharmacol 2017;70:129-41.
Penela P, Elorza A, Sarnago S, Mayor F
Jr., Beta-arrestin-and c-Src-dependent degradation of G-protein-coupled receptor kinase 2. EMBO J 2001;20:5129-38.
Han CC, Ma Y, Li Y, Wang Y, Wei W. Regulatory effects of GRK2 on GPCRs and non-GPCRs and possible use as a drug target (Review). Int J Mol Med 2016;38:987-94.
Traynham CJ, Hullmann J, Koch WJ. “Canonical and non-canonical actions of GRK5 in the heart”. J Mol Cell Cardiol 2016;92:196-202.
van der Westhuizen ET, Breton B, Christopoulos A, Bouvier M. Quantification of ligand bias for clinically relevant β2-adrenergic receptor ligands: Implications for drug taxonomy. Mol Pharmacol 2014;85:492-509.
Gaidarov I, Adams J, Frazer J, Anthony T, Chen X, Gatlin J, et al.
Angiotensin (1-7) does not interact directly with MAS1, but can potently antagonize signaling from the AT1 receptor. Cell Signal 2018;50:9-24.
Hayashi H, Hess DT, Zhang R, Sugi K, Gao H, Tan BL, et al.
S-nitrosylation of β-arrestins biases receptor signaling and confers ligand independence. Mol Cell 2018;70:473-87.e6.
Grisanti LA, Schumacher SM, Tilley DG, Koch WJ. Designer approaches for G protein-coupled receptor modulation for cardiovascular disease. JACC Basic Transl Sci 2018;3:550-62.
Dogra S, Sona C, Kumar A, Yadav PN. Epigenetic regulation of G protein coupled receptor signaling and its implications in psychiatric disorders. Int J Biochem Cell Biol 2016;77:226-39.
Hauser AS, Attwood MM, Rask-Andersen M, Schiöth HB, Gloriam DE. Trends in GPCR drug discovery: New agents, targets and indications. Nat Rev Drug Discov 2017;16:829-42.
Chaturvedi M, Schilling J, Beautrait A, Bouvier M, Benovic JL, Shukla AK, et al.
Emerging paradigm of intracellular targeting of G protein-coupled receptors. Trends Biochem Sci 2018;43:533-46.
[Table 1], [Table 2]