Adrenal G protein-coupled receptor kinase-2 in regulation of sympathetic nervous system activity in heart failure

Abstract

Heart failure (HF), the number one cause of death in the western world, is caused by the insufficient performance of the heart leading to tissue underperfusion in response to an injury or insult. It comprises complex interactions between important neurohormonal mechanisms that try but ultimately fail to sustain cardiac output. The most prominent such mechanism is the sympathetic (adrenergic) nervous system (SNS), whose activity and outflow are greatly elevated in HF. SNS hyperactivity confers significant toxicity to the failing heart and markedly increases HF morbidity and mortality via excessive activation of adrenergic receptors, which are G protein-coupled receptors. Thus, ligand binding induces their coupling to heterotrimeric G proteins that transduce intracellular signals. G protein signaling is turned-off by the agonist-bound receptor phosphorylation courtesy of G protein-coupled receptor kinases (GRKs), followed by βarrestin binding, which prevents the GRK-phosphorylated receptor from further interaction with the G proteins and simultaneously leads it inside the cell (receptor sequestration). Recent evidence indicates that adrenal GRK2 and βarrestins can regulate adrenal catecholamine secretion, thereby modulating SNS activity in HF. The present review gives an account of all these studies on adrenal GRKs and βarrestins in HF and discusses the exciting new therapeutic possibilities for chronic HF offered by targeting these proteins pharmacologically.

Keywords: G protein-coupled receptor, G protein-coupled receptor kinase, Heart failure, Sympathetic nervous system, Adrenergic receptor, Adrenal medulla

Core tip: The present manuscript is a mini-review describing the current knowledge in the field of adrenal GRKs and βarrestins, both of which are protein families that regulate adrenergic receptor function throughout the cardiovascular system. We specifically discuss the roles of these proteins in the adrenal medulla, as they pertain to regulation of catecholamine secretion and of sympathetic activity in chronic heart failure (HF). We also outline the exciting new possibilities of targeting these molecules in the adrenal glands for HF therapy.