Regulation of GPCR signaling in hypertension

Abstract

Hypertension represents a complex, multifactorial disease and contributes to the major causes of morbidity and mortality in industrialized countries: ischemic and hypertensive heart disease, stroke, peripheral atherosclerosis and renal failure. Current pharmacological therapy of essential hypertension focuses on the regulation of vascular resistance by inhibition of hormones such as catecholamines and angiotensin II, blocking them from receptor activation. Interaction of G-protein coupled receptor kinases (GRKs) and regulator of G-protein signaling (RGS) proteins with activated G-protein coupled receptors (GPCRs) effect the phosphorylation state of the receptor leading to desensitization and can profoundly impair signaling. Defects in GPCR regulation via these modulators have severe consequences affecting GPCR-stimulated biological responses in pathological situations such as hypertension, since they fine-tune and balance the major transmitters of vessel constriction versus dilatation, thus representing valuable new targets for anti-hypertensive therapeutic strategies. Elevated levels of GRKs are associated with human hypertensive disease and are relevant modulators of blood pressure in animal models of hypertension. This implies therapeutic perspective in a disease that has a prevalence of 65million in the United States while being directly correlated with occurrence of major adverse cardiac and vascular events. Therefore, therapeutic approaches using the inhibition of GRKs to regulate GPCRs are intriguing novel targets for treatment of hypertension and heart failure.

Figure 1

Overview of GPCR signalling cascade resulting in vasodilation or vasoconstriction: Within the present review we have outlined activation of GPCRs via a wide range of agonists, leading to activation of adenylyl cyclase (AC) via Gαs as well as guanylate cyclase (GC), increased 2nd messenger concentrations finally leading to protein kinase A or G-mediated vasodilation. Vasoconstrictory agents lead to activation of Gq and G12/13, which mediates smooth muscle con-traction via Protein Kinase C (PKC) or Rho Kinase as well as increased Ca²⁺, leading to inactivation of the myosin- light-chain kinase (MLCK) by dephosphorylation.