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Review
. 2013 Oct 11:7:1209-22.
doi: 10.2147/DDDT.S35905. eCollection 2013.

Current and future G protein-coupled receptor signaling targets for heart failure therapy

Ashley Siryk-Bathgate  1 , Samalia Dabul, Anastasios Lymperopoulos
Affiliations
Review

Current and future G protein-coupled receptor signaling targets for heart failure therapy

Ashley Siryk-Bathgate et al. Drug Des Devel Ther. .

Abstract

Although there have been significant advances in the therapy of heart failure in recent decades, such as the introduction of β-blockers and antagonists of the renin-angiotensin-aldosterone system, this devastating disease still carries tremendous morbidity and mortality in the western world. G protein-coupled receptors, such as β-adrenergic and angiotensin II receptors, located in the membranes of all three major cardiac cell types, ie, myocytes, fibroblasts, and endothelial cells, play crucial roles in regulation of cardiac function in health and disease. Their importance is reflected by the fact that, collectively, they represent the direct targets of over one-third of the currently approved cardiovascular drugs used in clinical practice. Over the past few decades, advances in elucidation of the signaling pathways they elicit, specifically in the heart, have led to identification of an increasing number of new molecular targets for heart failure therapy. Here, we review these possible targets for heart failure therapy that have emerged from studies of cardiac G protein-coupled receptor signaling in health and disease, with a particular focus on the main cardiac G protein-coupled receptor types, ie, the β-adrenergic and the angiotensin II type 1 receptors. We also highlight key issues that need to be addressed to improve the chances of success of novel therapies directed against these targets.

Keywords: G protein-coupled receptor; cardiac; heart failure; signaling; therapeutic target.

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Figures

Figure 1
Figure 1
G protein-coupled receptors and their signaling pathways involved in heart failure pathophysiology. Abbreviations: Aldo, aldosterone; AM, adrenomedullin; AR, adrenoceptor; AT1R, angiotensin II type 1 receptor; CRFR, corticotrophin-releasing factor receptor; DAG, 2-diacylglycerol; EGFR, epidermal growth factor receptor; Epi, epinephrine; GCGR, glucagon receptor; GLP1R, glucagon-like peptide-1 receptor; GPCRs, G protein-coupled receptors; GRK, GPCR kinase; NE, norepinephrine; PDE, phosphodiesterase; RXFP, relaxin family peptide; SNS, sympathetic nervous system; ???, indicates effect currently under investigation; βarr, beta arrestin; Gs, stimulatory G protein; Gi/Go, inhibitory/other G protein; Rho, Ras homolog gene family member A; Epac, exchange protein directly activated by cAMP; AC, adenylate cyclase; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C; V1R, vasopressin receptor type 1; RhoK, Rho-dependent kinase.
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