Cardiovascular GPCR regulation by regulator of G protein signaling proteins

Lymperopoulos, Anastasios; Suster, Malka S.; Borges, Jordana I.

doi:10.1016/bs.pmbts.2022.06.006

Cited by 4 publications

(5 citation statements)

References 107 publications

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“… 103 , 104 cAMP also enhances depolarizing Ca 2+ influx currents in AV nodal cells ( via PKA-mediated phosphorylation and opening of L-type calcium channels and of ryanodine receptor 2 channels), which is responsible for propagation of electrical conduction throughout the atria, AV node, and over to the ventricles (Purkinje fibers and Hiss bundle). 26 , 27 , 94 , 105 In other words, cAMP lowering reduces automaticity and induces negative dromotropy in the heart. RGS4 and RGS6 have long been known to function as key regulators of cholinergic control of HR.…”

Section: Therapeutic Potential Of Cardiac Rgs4mentioning

confidence: 99%

“…[20][21][22] This is why the cell utilizes 'regulator of G protein signaling (RGS)' domain-containing proteins, a ~120amino acid-long domain that can bind the Gα subunit and dramatically accelerate GTP hydrolysis. [20][21][22][23][24][25][26][27][28][29][30] The proteins that contain this RGS domain, first discovered in yeast and in the nematode worm Caenorhabditis elegans, are called RGS proteins. [20][21][22][23][24][25][26][27][28][29][30] GTP hydrolysis is enormously (up to 2000 times higher) accelerated by RGS proteins, and both the amplitude and duration of Gα and free Gβγ subunit signaling are markedly reduced.…”

Section: Introductionmentioning

confidence: 99%

“…[20][21][22][23][24][25][26][27][28][29][30] The proteins that contain this RGS domain, first discovered in yeast and in the nematode worm Caenorhabditis elegans, are called RGS proteins. [20][21][22][23][24][25][26][27][28][29][30] GTP hydrolysis is enormously (up to 2000 times higher) accelerated by RGS proteins, and both the amplitude and duration of Gα and free Gβγ subunit signaling are markedly reduced. 12,31 Every protein with a functional RGS domain is categorized into a subfamily, designated by a letter (A-F) and the name of a representative member of that particular subfamily (next to the letter 'R').…”

Section: Introductionmentioning

confidence: 99%

“… 36 Some RGS proteins, for example, RGS4 or RGS2, also interfere with the interaction of active (GTP-bound) Gα subunits with downstream effectors. 26 By acting as GTPase-activating proteins (GAPs) on Gα subunits, RGS proteins also accelerate free Gβγ signaling termination, since the heterotrimer reassembles. 26 , 27 It was initially thought that there might be a specific RGS protein for each of the 16 different Gα subunits but we now know that this could not have been further from the truth.…”

Section: Introductionmentioning

confidence: 99%

“… 26 By acting as GTPase-activating proteins (GAPs) on Gα subunits, RGS proteins also accelerate free Gβγ signaling termination, since the heterotrimer reassembles. 26 , 27 It was initially thought that there might be a specific RGS protein for each of the 16 different Gα subunits but we now know that this could not have been further from the truth. 27 Not only do the RGS proteins outnumber the Gα subunits, but also several of them can act upon more than one Gα type/family (e.g.…”

Section: Introductionmentioning

confidence: 99%

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The therapeutic potential of targeting cardiac RGS4

Del Calvo,

Baggio Lopez,

Lymperopoulos

2023

Therapeutic Advances in Cardiovascular Disease

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G protein-coupled receptors (GPCRs) play pivotal roles in regulation of cardiac function and homeostasis. To function properly, every cell needs these receptors to be stimulated only when a specific extracellular stimulus is present, and to be silenced the moment that stimulus is removed. The regulator of G protein signaling (RGS) proteins are crucial for the latter to occur at the cell membrane, where the GPCR normally resides. Perturbations in both activation and termination of G protein signaling underlie numerous heart pathologies. Although more than 30 mammalian RGS proteins have been identified, each RGS protein seems to interact only with a specific set of G protein subunits and GPCR types/subtypes in any given tissue or cell type, and this applies to the myocardium as well. A large number of studies have provided substantial evidence for the roles various RGS proteins expressed in cardiomyocytes play in cardiac physiology and heart disease pathophysiology. This review summarizes the current understanding of the functional roles of cardiac RGS proteins and their implications for the treatment of specific heart diseases, such as heart failure and atrial fibrillation. We focus on cardiac RGS4 in particular, since this isoform appears to be selectively (among the RGS protein family) upregulated in human heart failure and is also the target of ongoing drug discovery efforts for the treatment of a variety of diseases.

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Section: Therapeutic Potential Of Cardiac Rgs4mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The therapeutic potential of targeting cardiac RGS4

Del Calvo,

Baggio Lopez,

Lymperopoulos

2023

Therapeutic Advances in Cardiovascular Disease

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RGS proteins and cardiovascular Angiotensin II Signaling: Novel opportunities for therapeutic targeting

Lymperopoulos,

Borges,

Stoicovy

2023

Biochemical Pharmacology

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RGS Proteins in Sympathetic Nervous System Regulation: Focus on Adrenal RGS4

Lymperopoulos,

Stoicovy

2024

Front. Biosci. (Landmark Ed)

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The sympathetic nervous system (SNS) consists largely of two different types of components: neurons that release the neurotransmitter norepinephrine (NE, noradrenaline) to modulate homeostasis of the innevrvated effector organ or tissue and adrenal chromaffin cells, which synthesize and secrete the hormone epinephrine (Epi, adrenaline) and some NE into the blood circulation to act at distant organs and tissues that are not directly innervated by the SNS. Like almost every physiological process in the human body, G protein-coupled receptors (GPCRs) tightly modulate both NE release from sympathetic neuronal terminals and catecholamine (CA) secretion from the adrenal medulla. Regulator of G protein Signaling (RGS) proteins, acting as guanosine triphosphatase (GTPase)-activating proteins (GAPs) for the Gα subunits of heterotrimeric guanine nucleotide-binding proteins (G proteins), play a central role in silencing G protein signaling from a plethora of GPCRs. Certain RGS proteins and, in particular, RGS4, have been implicated in regulation of SNS activity and of adrenal chromaffin cell CA secretion. More specifically, recent studies have implicated RGS4 in regulation of NE release from cardiac sympathetic neurons by means of terminating free fatty acid receptor (FFAR)-3 calcium signaling and in regulation of NE and Epi secretion from the adrenal medulla by means of terminating cholinergic calcium signaling in adrenal chromaffin cells. Thus, in this review, we provide an overview of the current literature on the involvement of RGS proteins, with a particular focus on RGS4, in these two processes, i.e., NE release from sympathetic nerve terminals & CA secretion from adrenal chromaffin cells. We also highlight the therapeutic potential of RGS4 pharmacological manipulation for diseases characterized by sympathetic dysfunction or SNS hyperactivity, such as heart failure and hypertension.

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Cardiovascular GPCR regulation by regulator of G protein signaling proteins

Cited by 4 publications

References 107 publications

The therapeutic potential of targeting cardiac RGS4

The therapeutic potential of targeting cardiac RGS4

RGS proteins and cardiovascular Angiotensin II Signaling: Novel opportunities for therapeutic targeting

RGS Proteins in Sympathetic Nervous System Regulation: Focus on Adrenal RGS4

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