Heterotrimeric G protein-mediated signaling and its non-canonical regulation in the heart

Abstract

Heterotrimeric guanine nucleotide-binding proteins (G proteins) regulate a multitude of signaling pathways in mammalian cells by transducing signals from G protein-coupled receptors (GPCRs) to effectors, which in turn regulate cellular function. In the myocardium, G protein signaling occurs in all cardiac cell types and is centrally involved in the regulation of heart rate, pump function, and vascular tone and in the response to hemodynamic stress and injury. Perturbations in G protein-mediated signaling are well known to contribute to cardiac hypertrophy, failure, and arrhythmias. Most of the currently used drugs for cardiac and other diseases target GPCR signaling. In the canonical G protein signaling paradigm, G proteins that are located at the cytoplasmic surface of the plasma membrane become activated after an agonist-induced conformational change of GPCRs, which then allows GTP-bound Gα and free Gβγ subunits to activate or inhibit effector proteins. Research over the past two decades has markedly broadened the original paradigm with a GPCR-G protein-effector at the cell surface at its core by revealing novel binding partners and additional subcellular localizations for heterotrimeric G proteins that facilitate many previously unrecognized functional effects. In this review, we focus on non-canonical and epigenetic-related mechanisms that regulate heterotrimeric G protein expression, activation, and localization and discuss functional consequences using cardiac examples where possible. Mechanisms reviewed involve microRNAs, histone deacetylases, chaperones, alternative modes of G protein activation, and posttranslational modifications. Some of these newly characterized mechanisms may be further developed into novel strategies for the treatment of cardiac disease and beyond.

Keywords: Epigenetic; G protein; Heart; Localization; MicroRNA; Non-canonical; Posttranslational modification; Regulation; Signal transduction.

Fig. 1

Schematic depiction of the regulation of heterotrimeric G protein signaling. Activation/inactivation cycle for heterotrimeric G proteins (A) and regulatory mechanism involved in the modulation of G protein signaling (B). See text for details. Abbreviations: AGS — activators of G protein signaling, GDP — guanosine diphosphate, GTP — guanosine triphosphate, GPCR — G protein-coupled receptor, NDP — nucleoside diphosphate, NDPK — nucleoside diphosphate kinase, NTP — nucleoside triphosphate, Pi — phosphate (inorganic), RGS — regulators of G protein Signaling.