Table 1 GRK substrates related to the regulation of blood pressure

From: G protein-coupled receptor kinases in hypertension: physiology, pathogenesis, and therapeutic targets

GRK isoform	Substrate protein	Tissue/cells	Regulation of Substrate
GPCR substrates
GRK2	ETAR	Rat mesenteric arterial smooth muscle cells [35]; rat aortic smooth muscle cells [37]	Inactive dominant-negative GRK2 or siRNA-Grk2 attenuates ETAR desensitization and its mediated VSMC contractile or migration signaling [35, 37]
	P2Y₂R	Rat mesenteric artery [36]; rat mesenteric arterial smooth muscle cells [36]; rat aortic smooth muscle cells [37]	GRK2 inhibition or siRNA-Grk2 attenuates P2Y₂R desensitization and its mediated VSMC contractile or migration signaling [36, 37]
	β-AR	Mouse aortic arterial smooth muscle cells [34]; brachial artery [66]; HEK293 cells [76]	VSM-targeted overexpression of Grk2 attenuates β-AR signaling and vasodilation [34]; inhibition of GRK2 activity prevents β-AR desensitization [66]; GRK2 directly interacts with β₂-AR and regulates its desensitization [76]; Grk2 knockout or GRK2 inhibition increases β-AR-mediated vasodilation [39]
	AT₁R	HEK293 cells [38]; kidney [43]; heart [32]	GRK2 inhibition reduces agonist-induced AT₁R phosphorylation and prevents receptor desensitization [38]; Grk2 knockdown enhances renal AT₁R-mediated ROS production [43]; cardiac-specific Grk2 expression attenuates Ang II-induced increase in cardiac contractility [32]
	D₁R	Rat RPT cells [47, 49]; OK cells [48]; HEK293 cells [41, 75] and rat striatum [75]	GRK2 mediates H₂O₂ or insulin-caused renal D₁R phosphorylation and impairs D₁R-mediated inhibition of Na⁺-K⁺-ATPase activity [47, 48]; GRK2 increases D₁R desensitization and phosphorylation [75]; Grk2 overexpression increases agonist-induced D₁R phosphorylation [41]
	α_1D-AR	VSM	Grk2 knockout or peptide inhibition enhances α_1D-AR-induced vasoconstriction [39]
GRK3	α₁-AR	Cardiac myocytes	GRK3 inhibition causes α₁-AR hyper-responsiveness [73]
	D₁R	HEK293 cells; rat striatum	GRK3 increases D₁R desensitization and phosphorylation [75]; Grk3 overexpression increases dopamine-induced D₁R phosphorylation [41]
	β₂-AR	HEK293 cells	GRK3 directly interacts with β₂-AR and regulates its desensitization [76]
	AT₁R	HEK293 cells	Grk3 overexpression increases angiotensin II-induced AT₁R phosphorylation [38]
GRK4	D₁R	CHO cells [15]; HEK293T cells [85]; Human RPT cells[15, 86]; Kidney [81]; Rat renal cortex [79];	GRK4 phosphorylates the D₁R, causing its constitutive desensitization and internalization [85]; GRK4 As-Odns decrease serine-phosphorylated D₁R [79]; UTMD-mediated renal Grk4 siRNA delivery reduces D₁R phosphorylation and blood pressure and increases D₁R-mediated natriuresis and diuresis [81]; GRK4γ variants increase D₁R phosphorylation and impair D₁R-mediated cAMP production [15]; GRK4 inhibition blunts D₁R desensitization [86]
	D₃R	Human RPT cells	GRK4γ and GRK4α increase the phosphorylation of agonist-activated D₃R [91]
	AT₁R	Thoracic aortic VSM cells [77]; HEK293 cells and human RPT cells [78]; kidney [78]	hGRK4γ 142V increases AT₁R expression [77, 78]
	ETBR	Renal cortex; rat RPT cells	hGRK4γ 142V increases but GRK4 depletion decreases renal ETBR phosphorylation [82]
	AT₂R	Renal cortex; rat RPT cells	hGRK4γ 142V increases renal AT₂R phosphorylation and causes its dysfunction [93]
	CCKBR	Renal cortex; rat RPT cells	hGRK4γ 142V increases but GRK4 silencing decreases renal CCKBR phosphorylation [170]
GRK5	AT₁R	HEK293 cells	Grk5 overexpression increases the angiotensin II-induced AT₁R phosphorylation [38]
	β-AR	VSM [122]; heart [32]	VSM-Grk5 over-expression increases blood pressure to a greater extent in male than female mice; β-AR stimulation induced vasoconstriction in male mice but decreased β-AR-induced vasodilation and increased angiotensin II sensitivity in female mice [122]; Cardiac-specific Grk5 expression increases β-AR desensitization but does not affect the contractile response to angiotensin II [32]
	D₁R	HEK293 cells	Grk5 overexpression increases agonist-induced D₁R phosphorylation [41]
GRK6	D₁R	Intestinal epithelial cells	GRK6 antibodies prevents the desensitization-mediated loss of D₁R inhibition of Cl/HCO3^- exchanger activity [130]
Non-GPCR receptor substrates
GRK4	adipoR1	Renal cortex; rat RPT cells	hGRK4γ 142V causes adipoR1 phosphorylation and desensitization [21]
Non-receptor substrates
GRK2	ENaC	Salivary duct cells	GRK2 phosphorylates S633 in the C terminus of ENaC [44]
	Nedd4 and Nedd4-2	HEK293T cells	GRK2 phosphorylates Nedd4 and Nedd4-2 [46]
GRK4	HDAC4	Mouse cardiomyocytes	GRK4 increases HDAC4 phosphorylation and decreases its binding to the beclin-1 promoter [28]
	NF-κB	Embryonic rat thoracic aortic smooth muscle cells	GRK4γ 142V increases NF-κB activity with more NF-κB bound to the AT₁R promoter [77]
	STAT1	HK-2 cells and mouse kidney	GRK4 phosphorylates STAT1 [27]
	HDAC1	Human RPT cells and mouse kidney	GRK4γ 142V phosphorylates HDAC1 and promotes its nuclear export to the cytoplasm [78]

α-AR α-adrenergic receptor, adipoR1 adiponectin receptor 1, As-Odn antisense oligodeoxynucleotides, AT₁R angiotensin II type 1 receptor, AT₂R angiotensin II type 2 receptor, β-AR β-adrenergic receptor, cAMP cyclic adenosine monophosphate, CCKBR cholecystokinin receptor type B, CHO Chinese hamster ovary, D₁R dopamine D₁ receptor, ENaC epithelial sodium channel, ETAR endothelin receptor type A, ETBR endothelin receptor type B, GRK G protein-coupled receptor kinase, HDAC1 Histone deacetylase 1, HDAC4 Histone deacetylase 4, hGRK4γ human G protein-coupled receptor kinase 4-gamma, Nedd4 neural precursor cell expressed developmentally downregulated 4, NF-κB nuclear factor-κB, P2Y₂R P2Y₂ receptor, ROS reactive oxygen species, STAT1 signal transducer and activator of transcription 1, VSM vascular smooth muscle, VSMC vascular smooth muscle cell, UTMD ultrasound-targeted microbubble destruction

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Table 1 GRK substrates related to the regulation of blood pressure

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