G Protein–Dependent and G Protein–Independent Signaling Pathways and Their Impact on Cardiac Function

Abstract

G protein-coupled receptors (GPCRs) signal through a variety of mechanisms that impact cardiac function, including contractility and hypertrophy. G protein-dependent and -independent pathways each have the capacity to initiate numerous intracellular signaling cascades to mediate these effects. G protein-dependent signaling has been studied for decades and great strides continue to be made in defining the intricate pathways and effectors regulated by G proteins and their impact on cardiac function. G protein-independent signaling is a relatively newer concept that is being explored more frequently in the cardiovascular system. Recent studies have begun to reveal how cardiac function may be regulated via G protein-independent signaling, especially with respect to the ever-expanding cohort of β-arrestin-mediated processes. This review primarily focuses on the impact of both G protein-dependent and β-arrestin-dependent signaling pathways on cardiac function, highlighting the most recent data that illustrate the comprehensive nature of these mechanisms of GPCR signaling.

Transactivation of the epidermal growth factor receptor in responses to myocardial stress and cardioprotection

“…Other studies identify G protein independent/β-arrestin dependent mechanisms of EGFR activation (Tilley, 2011). Noma et al (2007) report β1-adrenoceptor transactivation of cardiomyocyte EGFR independently of G protein activation, involving β-arrestin recruitment via G protein-coupled receptor kinase (and a subsequent canonical cascade of EGFR transactivation involving Src, a metalloprotease, and HB-EGF shedding).…”

Focused Proteomics Revealed a Novel Rho-kinase Signaling Pathway in the Heart

“…Adaptive phosphorylation mediates the contraction and relaxation of cardiomyocytes to regulate cardiac pump function (Bers, 2002). Conversely, maladaptive phosphorylation causes cardiac diseases such as cardiac hypertrophy and heart failure (Tilley, 2011). Thus, analyzing the phosphorylation process could aid in better understanding of the physiological and pathological functions of the heart.…”

Discovery and validation of potential drug targets based on the phylogenetic evolution of GPCRs

“…These cellular processes in turn regulate systemic functions such as embryonic development, gonadal development, learning and memory, and organismal homeostasis [2]. G protein-dependent and G protein-independent pathways each have the capacity to initiate numerous intracellular signaling cascades to mediate these effects [4]. G proteins are GTPases (guanosine triphosphatases) that cycle between a GDP-bound form and a GTP-bound form [5].…”

“…The GTP-bound G protein is an active form that interacts with downstream effectors and transmits signals, during which the bound GTP is often hydrolyzed to GDP and the G protein recycles into the inactive GDP-bound form [5]. The heterotrimeric G protein complex comprises a Gα subunit, of which there are 4 main families (Gαs, Gαi/o, Gαq/11, and Gα12/13), coupled to a combination of Gβ and Gγ subunits, of which there exist 6 and 12 members, respecttively [2,4]. Gα subunit binds to guanine nucleotides while Gβγ subunits cannot be dissociated under nondenaturing conditions.…”