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.

Endogenous RGS14 is a cytoplasmic-nuclear shuttling protein that localizes to juxtanuclear membranes and chromatin-rich regions of the nucleus

“…We speculate that endogenous RGS14 is translated in the cytosol and then finds a newly acylated Gα binding partner tethered to the outer leaflet of ER/Golgi membranes. Consistent with this idea, the RGS14 binding partner Gαi3 is known to be present and enriched on the cytoplasmic face of both Golgi membranes and endosomes where is thought to play a role in regulating anterograde protein trafficking to the plasma membrane [ 44 , 65 ].…”

Targeting RGS4 Ablates Glioblastoma Proliferation

“…2020, 21, 3300 2 of 14 signaling of G-protein-coupled receptors is modulated by regulator of G-protein signaling (RGS) proteins that catalyze the dephosphorylation of guanosine triphosphate into guanosine diphosphate. Following cleavage of the third phosphate molecule and subsequent release of energy, regulator of G-protein signaling 4 (RGS4) locks the G-protein in its inactive guanosine diphosphate (GDP) state [19,20]. Here, we hypothesize that glioblastoma (GBM) tumors rely on GPCR regulation, making RGS4 an excellent candidate as a tumor-promoting gene.…”

Neurohumoral Control of Sinoatrial Node Activity and Heart Rate: Insight From Experimental Models and Findings From Humans

“…In general, these substances bind to a GPCR, causing a conformational change in its cytoplasmic domains, which activates its subunits (G α and G βγ ) (Oldham and Hamm, 2008;Rosenbaum et al, 2009;Zhang et al, 2015). The G α isoforms of primary importance in the SAN are G αs , G αi/o , and G αq/11 (Marin-Garcia, 2011).…”

“…Activation of G αq/11 on the other hand does not alter cAMP levels, but instead either G αq or G α11 activates phospholipase C (PLC), which breaks down phosphatidylinositol 4,5-bisphosphate (PIP 2 ) into diacylglycerol (DAG) and inositol triphosphate (IP 3 ), both of which affect multiple downstream targets (Marin-Garcia, 2011). And while the G α subunits initiate the primary signaling cascades, G βγ subunits may also be involved (Zhang et al, 2015). Another important signaling pathway in SAN myocytes occurs through particulate or soluble guanylyl cylcase (GC) activation, which results in cGMP activation and modulation of downstream targets by protein kinase G (PKG) or other downstream regulatory molecules (Zaccolo and Movsesian, 2007).…”