Table 1.

Summary of GRK Family and Hypertension

GRK Isoform	Tissue Distribution	GRK Modification	Effects of GRK Modification on Blood Pressure and Related GPCRs	GRK Expression and Activity in Hypertension
GRK2	Ubiquitous expression	VSM‐targeted overexpression	Impairs β‐AR induced vasodilation34; increases resting blood pressure34	Increased GRK2 expression and GRK activity in lymphocytes and arteries in hypertensive patients and SHRs60, 63, 64; increased GRK2 expression in conductance and resistance vessels in SHRs61, 117; decreased GRK2 expression in conductance vessels and no change in GRK2 expression in resistance vessels in L‐NAME‐ induced hypertensive rats61; increased GRK2 expression and GRK activity in mesenteric artery of sedentary SHRs43; increased renal GRK2 expression in obese rats29; increased renal GRK2 expression in offspring of lipopolysaccharide‐treated dams57
		Hemizygous mice (GRK2+/−)	No effect on baseline blood pressure but protects against Ang II–induced hypertension and vascular remodeling33
		Global knockdown using a shRNA	Results in spontaneous hypertension22; increases both vasoconstriction in response to PE and vasodilatation in response to β‐AR stimulation22
		VSMC‐specific ablation of GRK2	No effect on baseline blood pressure35; increases β‐AR–mediated vasodilation, but also enhances α1DAR‐stimulated vasoconstriction35
		Selective deletion of endothelial GRK2	Blood pressure not measured; blunts vasoconstriction to different agonists42
		Gene depletion Renal proximal tubule GRK2 gene depletion	Blunts desensitization of arterial ETAR46; promotes insulin‐induced vasodilation of mesenteric arteries in SHRs43blunts desensitization of renal proximal tubule D1R54
GRK3	Ubiquitous expression	Cardiac‐restricted GRK3 inhibition	Increases blood pressure and cardiac output67; increased cardiac myocyte α1‐AR responsiveness67; attenuates cardiac dysfunction caused by pressure overload24	No significant difference in GRK3 expression in the lymphocytes of hypertensive and normotensive patients9
GRK4	Testes, myometrium, brain, intestines, kidney, and artery	Overexpression of human GRK4142V	Increases blood pressure (normal salt diet)16, 77; impairs renal D1R function16; increases AT1R expression in the kidney and artery21, 77; increases in systolic blood pressure response to Ang II21	Increased renal GRK4 expression in SHRs72; increased renal GRK activity in hypertensive subjects16; increased renal GRK4 expression and normalized by rosiglitazone (insulin sensitizer) in obese Zucker rats55; increased renal GRK4 expression in offspring of lipopolysaccharide‐treated dams57
		Overexpression of human GRK4486V	Increases blood pressure (on high salt diet) and renal AT1R expression78; increases in basal D1R phosphorylation and impairs the function of D1R16
		Overexpression of human GRK465L	Increase basal D1R phosphorylation and impairs D1R‐mediated cAMP production16
		GRK4 gene depletion	Increases sodium excretion, attenuates the increased blood pressure and renal serine‐phosphorylated D1R in SHRs72; blunts the D1R desensitization in human RPTCs54; blocks D1R phosphorylation and restores D1R‐ mediated cAMP accumulation in RPTCs from hypertensive participants16
GRK5	Ubiquitous expression	VSM‐specific overexpression	Increases blood pressure23	Increased GRK5 expression in Ang II–treated VSMCs93; increased GRK5 expression in aortas of Ang II– and norepinephrine‐induced hypertension93; no significant difference in GRK5 expression in the lymphocytes of hypertensive and normotensive patients9
		Global knockout	Increases insulin resistance92
		Overexpression of GRK5	Increases agonist‐dependent phosphorylation of the AT1R or D1R97, 98
GRK6	Ubiquitous expression	Global knockout	Causes striatum D2R supersensitivit110	Decreased renal GRK6 expression in hypertensive participants and SHRs111; increased myocardial GRK6 expression in SHHF rats66
		Inhibition using antibody	Prevents intestinal D1R desensitization107

Ang II indicates angiotensin II; AR, adrenergic receptor; AT₁R, angiotensin II type 1 receptor; D₁R, dopamine D₁ receptor; ETAR, endothelin A receptor; GPCR, G protein–coupled receptor; GRK, G protein–coupled receptor kinase; PE, phenylephrine; RPTC, renal proximal tubule cell; SHHF, spontaneously hypertensive heart failure; SHR, spontaneously hypertensive rat; shRNA, small hairpin RNA; VSM, vascular smooth muscle; VSMC, vascular smooth muscle cell.