GRK2 in Lymphocytes: Expanding the Arsenal of Heart Failure Prognostics

Heart failure (HF) has been described as the inability of the myocardium to deliver oxygen and nutrients to a degree commensurate with the metabolic requirements of the body.1 Myocardial dysfunction induces compensatory neurohumoral mechanisms, including the sympathetic nervous system (SNS), as an attempt to preserve contractile performance. Mediators of the SNS consist predominantly of 2 catecholamines, namely epinephrine and norepinephrine (NE), released by cardiac sympathetic nerve terminals or secreted directly into the circulation by the adrenal medulla. Effects of these neurotransmitters are mediated through cell surface adrenergic receptors (ARs), members of the G protein–coupled receptor superfamily. Stimulation of the β-AR promotes a conformational change to activate the heterotrimeric G protein Gα and Gβγ subunits, promoting positive inotropic and chronotropic effects culminating in improved myocardial function.2 Article, see p 1116 This functionally beneficial pathway refers exclusively, however, to acute receptor activation; sustained β-AR stimulation, as occurs in most cardiovascular disease, is characterized by molecular modifications, leading to reduced receptor sensitivity and membrane expression. Receptor desensitization and downregulation are regulatory processes thought to moderate persistent agonist stimulation to prevent catecholamine-induced toxicity. The desensitization process is initiated in large part by agonist-dependent phosphorylation of the receptor’s cytoplasmic tail by G protein–coupled receptor kinase 2 (GRK2), a serine/threonine kinase. GRK2 is a cytosolic enzyme that localizes to the plasma membrane after recruitment by active Gβγ subunits. This is followed by recruitment of β-arrestin to the phosphorylated receptor, which prevents recoupling of the dissociated cognate G protein and targets the receptor for internalization and eventual degradation. It is now appreciated that chronic SNS activity and subsequent GRK2-mediated receptor downregulation result in a loss of responsiveness to catecholamines and contribute to further contractile dysfunction and increased patient mortality.2,3 Pivotal studies have indicated that properties of β-AR signaling seem …