Cardiac GPCRs: GPCR signaling in healthy and failing hearts

Abstract

G protein-coupled receptors (GPCRs) are widely implicated in human heart disease, making them an important target for cardiac drug therapy. The most commonly studied and clinically targeted cardiac GPCRs include the adrenergic, angiotensin, endothelin, and adenosine receptors. Treatment options focusing on the complex and integrated signaling pathways of these GPCRs are critical for the understanding and amelioration of heart disease. The focus of this review is to highlight the most commonly studied and clinically targeted cardiac GPCRs, placing emphasis on their common signaling components implicated in cardiac disease.

Figure 1. Overview of GPCR Signaling

Agonist binding to receptor results in the coupling to a G-protein and the conversion of GTP to GDP to cause the dissociation of Gα and Gβγ subunits. Gα signaling is initiated with the activation of a membrane-bound effector molecule, such as adenylyl cyclase (AC) or phospholipase C β (PLCβ) to produce second messengers such as cyclic adenosine 3′,5′ monophosphate, (cAMP), diacylglycerol (DAG), or inositol 1,4, 5-triphosphate (IP₃), which activate a variety of downstream signals with a range of physiological consequences in the heart such as the regulation of contractility, hypertrophy, and apoptosis. A simultaneous process involves the ligand-activated translocation of G protein-coupled receptor kinases (GRKs) and bound phosphoinositide-3-kinase (PI3K), to the membrane by dissociated Gβγ subunits leading to receptor phosphorylation on the C-terminal tail. Following GRK mediated receptor phosphorylation, β-arrestin is bound and acts to 1) desensitize G protein signaling by uncoupling the receptor from G protein, 2) scaffold for the recruitment of proteins involving in receptor trafficking, such as AP2, clathrin, and dynamin, and 3) form a signaling complex that initiates G protein-independent downstream signaling such as the activation of mitogen-activated protein (MAP) kinases.

Figure 2. G_s/G_i-coupled receptor signaling

G_s- and G_i-coupled receptors target the second messenger adenylyl cyclase (AC). While G_s stimulates AC, activation of G_i inhibits AC, reducing the accumulation of cAMP and consequently leading to reduced PKA and agonist-stimulated cardiac contractility. Downstream effectors of Gα_s activation result from the increase in PKA which phosphorylation substrates include: phospholamban (PLN), troponin, L-type Ca²⁺ channels, and the cardiac ryanodine receptor (RyR2).

Figure 3. G_q-coupled receptor signaling

G_q-coupled receptors such as endothelin, angiotensin, or α-1-adrenergic receptors activate the second messenger phospholipase C β resulting in the hydrolysis of phosphatidylinositol 4, 5 biphosphate (PIP₂) into two components: diacylglycerol (DAG) and inositol 1, 4, 5-triphosphate (IP₃). DAG activates several isoforms of protein kinase C (PKC). PKCβ activation regulates hypertrophy, contractility, and neonatal cardiac growth. PKCσ activation regulates postischemic necrosis and contractile function. PKCε activation induces a cardioprotective effect in response to ischemic preconditioning. Activation of Gq-coupled receptors stimulates the release of calcium, which activates CaMKII and calcineurin to promote the nuclear translocation of nuclear factor of activated T-cells (NFAT) whereby the hypertrophic transcriptional machinery is activated.