Skip to main page content
U.S. flag

An official website of the United States government

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Mar 24;24(7):6136.
doi: 10.3390/ijms24076136.

Cardiac RGS Proteins in Human Heart Failure and Atrial Fibrillation: Focus on RGS4

Jordana I Borges  1 , Malka S Suster  1 , Anastasios Lymperopoulos  1
Affiliations
Review

Cardiac RGS Proteins in Human Heart Failure and Atrial Fibrillation: Focus on RGS4

Jordana I Borges et al. Int J Mol Sci. .

Abstract

The regulator of G protein signaling (RGS) proteins are crucial for the termination of G protein signals elicited by G protein-coupled receptors (GPCRs). This superfamily of cell membrane receptors, by far the largest and most versatile in mammals, including humans, play pivotal roles in the regulation of cardiac function and homeostasis. Perturbations in both the activation and termination of their G protein-mediated signaling underlie numerous heart pathologies, including heart failure (HF) and atrial fibrillation (AFib). Therefore, RGS proteins play important roles in the pathophysiology of these two devasting cardiac diseases, and several of them could be targeted therapeutically. Although close to 40 human 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. Numerous in vitro and in vivo studies in animal models, and also in diseased human heart tissue obtained from transplantations or tissue banks, have provided substantial evidence of the roles various cardiomyocyte RGS proteins play in cardiac normal homeostasis as well as pathophysiology. One RGS protein in particular, RGS4, has been reported in what are now decades-old studies to be selectively upregulated in human HF. It has also been implicated in protection against AFib via knockout mice studies. This review summarizes the current understanding of the functional roles of cardiac RGS proteins and their implications for the treatment of HF and AFib, with a specific focus on RGS4 for the aforementioned reasons but also because it can be targeted successfully with small organic molecule inhibitors.

Keywords: G protein-coupled receptor; atrial fibrillation; cardiac myocyte; cyclic AMP; heart failure; regulator of G protein signaling-4; signal transduction.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Role of cardiomyocyte RGS4 in the context of human HF. Gαi activity is high and cAMP levels are low in the failing human heart. Phosphorylation of MyBPC3 by PKA first increases contraction before it facilitates relaxation of the actin-myosin fibers. ACh: acetylcholine; AC: adenylyl cyclase; Pi: inorganic phosphate; P: phosphorylation; NKA: Na+/K+-adenosine triphosphatase (sodium pump); PLM: phospholemman; PLN: phospholamban; ATP: adenosine triphosphate; SR: sarcoplasmic reticulum; SERCA: sarco(endo)plasmic reticulum calcium adenosine triphosphatase; A: adenine; G: guanine; R: regulatory subunit of PKA; C: catalytic subunit of PKA. See text for details and all other molecular acronym descriptions.
Figure 2
Figure 2
Role of (atrial) cardiomyocyte RGS4 in the context of human AFib. Note that the free Gi/o-protein-derived Gβγ dimer can also activate certain isoforms of PLCβ directly. Also depicted is the inhibitory effect of RGS4 on NLRP3 inflammasome (indirectly, via enhanced PKA-dependent phosphorylation) which awaits experimental confirmation. AngII: angiotensin II; ACh: acetylcholine; IP3: inositol 1′, 4′, 5′-trisphosphate; Pi: inorganic phosphate; ASC: apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD); Pro-Casp-1: pro-caspase-1; HR: heart rate. See text for details and all other molecular acronym descriptions.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Insel P.A., Sriram K., Gorr M.W., Wiley S.Z., Michkov A., Salmerón C., Chinn A.M. GPCRomics: An Approach to Discover GPCR Drug Targets. Trends Pharmacol. Sci. 2019;40:378–387. doi: 10.1016/j.tips.2019.04.001. - DOI - PMC - PubMed
    1. Sriram K., Insel P.A. G Protein-Coupled Receptors as Targets for Approved Drugs: How Many Targets and How Many Drugs? Mol. Pharmacol. 2018;93:251–258. doi: 10.1124/mol.117.111062. - DOI - PMC - PubMed
    1. Li J., Ge Y., Huang J.-X., Strømgaard K., Zhang X., Xiong X.-F. Heterotrimeric G Proteins as Therapeutic Targets in Drug Discovery. J. Med. Chem. 2019;63:5013–5030. doi: 10.1021/acs.jmedchem.9b01452. - DOI - PubMed
    1. Hauser A.S., Attwood M.M., Rask-Andersen M., Schiöth H.B., Gloriam D.E. Trends in GPCR drug discovery: New agents, targets and indications. Nat. Rev. Drug Discov. 2017;16:829–842. doi: 10.1038/nrd.2017.178. - DOI - PMC - PubMed
    1. Weis W.I., Kobilka B.K. The Molecular Basis of G Protein–Coupled Receptor Activation. Annu. Rev. Biochem. 2018;87:897–919. doi: 10.1146/annurev-biochem-060614-033910. - DOI - PMC - PubMed