G Protein–Coupled Receptor Kinase 4

Abstract

N early 30% of middle-aged Americans have hypertension, but the prevalence is higher in non-Hispanic blacks and individuals Ͼ60 years of age (65%). 1 There is a direct and quantitative relationship between higher blood pressure values and mortality. Although 30% to 50% is thought to be heritable, the genetic cause(s) of essential hypertension has been difficult to identify. More than 1 gene is undoubtedly involved, because Mendelian dominant and recessive traits are not readily discernible in hypertensive subjects, except in those with monogenic forms of hypertension. Moreover, in any hypertensive individual, risk-predisposing genes are engaged in a complex network of gene-gene and geneenvironment interactions. 2,3 The kidney plays a major role in the long-term regulation of blood pressure, and abnormal sodium chloride metabolism is frequently encountered in hypertension. Therefore, many studies have focused on the abnormal renal handling of sodium chloride in the pathogenesis of essential hypertension. 2,4 Approximately 50% of subjects with essential hypertension are sodium chloride sensitive. 5 Indeed, humans with salt-sensitive hypertension have increased sodium transport in the renal proximal tubule and medullary thick ascending limb, although distal tubular mechanisms may also be involved. 6 The sodium retention in hypertension is because of enhanced sodium transport, per se, and/or a failure to respond appropriately to signals that decrease sodium transport. Sodium transport is regulated by natriuretic and antinatriuretic hormones and humoral agents, such as dopamine and angiotensin, which exert their effects via G protein-coupled receptors (GPCRs). Activation of certain postjunctional dopamine receptor subtypes (D 1 R, D 3 R, D 4 R, and D 5 R) and the angiotensin type 2 receptor inhibit, whereas activation of the postjunctional D 2 R and angiotensin type 1 receptor (AT 1 R) increase sodium transport. 2,7 GPCR Kinase FamilyThe GPCR kinases (GRKs) are a 7-member family of serine/threonine protein kinases characterized by their ability to phosphorylate or modify and desensitize agonist-occupied cell surface membrane GPCRs. GRKs 1 and 7 belong to the rhodopsin family; GRKs 2 and 3 belong to the ␤-adrenergic receptor kinase family, and GRKs 4, 5, and 6 belong to the GRK4 family (Table 1). GRKs 1 and 7 are expressed exclusively in rods and cones, respectively, in the retina. GRKs 2, 3, 5, and 6 are ubiquitously expressed, whereas GRK4 expression is limited (see below). 8 Overexpression of GRK2, GRK3, and especially GRK5 in human embryonic kidney cells desensitizes the D 1 R. 9 GRK activity and GRK2 expression are increased in lymphocytes of patients with essential hypertension and spontaneously hypertensive rats (SHRs). 10 Overexpression of GRK2 in vascular smooth muscles in mice produces hypertension and impairs the vasodilatory action of ␤-adrenergic receptors. 11 The vasoconstrictor response to angiotensin II is also impaired in these mice, which is at odds with the increased reactivity and sensitivity to an...

Role of GRK4 in the Regulation of Arterial AT1 Receptor in Hypertension

“…GRK4 variants, including 65L, 142V, and 486V, by themselves, or interaction with other variants of other genes are associated with hypertension in American Caucasians 39 , Australian Caucasians 12 , Italians 36 and northern Han Chinese 40 . We have reported that hGRK4γ 142V transgenic mice on 98% C57BL/6J background are hypertensive relative to non-transgenic littermates and hGRK4γ WT transgenic mice 6,8,11,13,34 . To further investigate the role of GRK4 variants on the hypertension, we generated hGRK4γ 142V and GRK4γ WT transgenic mice on C57BL/6J and SJL/J background.…”

“…The GRK4 locus (4p16.3) is linked to and GRK4 gene variants are associated with human essential hypertension 4,6,8,11,12,[36][37][38] . In Ghanaians, the two-locus model of angiotensin converting enzyme I/D and GRK4 65L predicts the hypertensive phenotype 70.5% of the time 37 .…”

“…The kidney, vasculature, and nervous system govern the long-term control of blood pressure by regulating sodium homeostasis, peripheral resistance, and central arterial stiffness [3][4][5] ; they, in turn, are influenced by numerous hormones and neural and humoral factors. Hypertension may be caused not only by increased activity of pro-hypertensive systems but also by defects in anti-hypertensive systems that serve as counter-regulatory mechanisms 4,[6][7][8] . Most hormones and humoral factors regulate blood pressure via their receptors, including G protein-coupled receptors (GPCRs).…”

“…Most hormones and humoral factors regulate blood pressure via their receptors, including G protein-coupled receptors (GPCRs). GPCRs comprise the largest family of cell surface receptors [6][7][8] ; abnormal G protein-coupled receptor kinase (GRK) function has the potential to affect receptor-regulated biological responses in many physiological and pathological conditions, including hypertension 4,5,7 .…”

G Protein-coupled Receptor Kinase 4 (GRK4) Regulates the Phosphorylation and Function of the Dopamine D3 Receptor

“…This may also be true for D 3 R. The requirement for GRK4, in its capacity to phosphorylate and/or properly position the receptor in the membrane, may explain the inhibitory effect of heparin or of decreased GRK4 expression on D 3 R-induced mitogenesis and also opens new views into the role of receptor phosphorylation on signal transduction. However, persistently increased constitutive GRK4 activity results in desensitization of D 1 R, seen in human essential hypertension (1,13,17). Whether a similar state occurs with the D 3 R remains to be determined.…”