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Last update 08 May 2025

GRK2

Last update 08 May 2025

Basic Info

Synonyms

ADRBK1, adrenergic, beta, receptor kinase 1, BARK

+ [6]

Introduction

Specifically phosphorylates the agonist-occupied form of the beta-adrenergic and closely related receptors, probably inducing a desensitization of them (PubMed:19715378). Key regulator of LPAR1 signaling (PubMed:19306925). Competes with RALA for binding to LPAR1 thus affecting the signaling properties of the receptor (PubMed:19306925). Desensitizes LPAR1 and LPAR2 in a phosphorylation-independent manner (PubMed:19306925). Positively regulates ciliary smoothened (SMO)-dependent Hedgehog (Hh) signaling pathway by facilitating the trafficking of SMO into the cilium and the stimulation of SMO activity (By similarity). Inhibits relaxation of airway smooth muscle in response to blue light (PubMed:30284927).

Drugs associated with GRK2

GRK2 PROTAC(Sonata)

Target

GRK2

Mechanism

GRK2 inhibitors

Active Org.-

Originator Org.

Sonata Therapeutics, Inc.

Active Indication-

Inactive Indication

Pancreatic Cancer

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

CCG-224406

Target

GRK2

Mechanism

GRK2 inhibitors

Active Org.-

Originator Org.

Temple University Graduate School

Active Indication-

Inactive Indication

Heart Failure

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

CCG215022

Target

GRK2 x GRK5

Mechanism

GRK2 inhibitors [+1]

Active Org.-

Originator Org.

University of Michigan

Active Indication-

Inactive Indication

Cardiovascular Diseases

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with GRK2

100 Translational Medicine associated with GRK2

0 Patents (Medical) associated with GRK2

1,596

Literatures (Medical) associated with GRK2

01 Dec 2025·Molecular Biology Reports

Novel role of GRK2 in isoprenaline-induced activation of Na+/H+ exchanger 3 independent of β2-adrenergic receptor signaling

Article

Author: Huang, Jing ; Dai, Yongfa ; Lai, Xiaomei ; Wen, Hong ; Li, Jianling

BACKGROUNDThe activation of Na⁺/H⁺ exchanger 3 (NHE3) by β2-adrenergic receptor (β2-AR) signaling is well-established. Our research indicates that isoprenaline (ISO) induces activation of NHE3 independent of β2AR signaling but through a different way that has not been elucidated before.METHODSThe activation of NHE3 in HK-2 cell lines was quantified using the fluorescence probe BCECF/AM. The expression levels of G protein-coupled receptor kinase 2 (GRK2) and its downstream effector, β-arrestin 1 (ARRB1), were assessed through Western blot analysis and immunohistochemical staining. ISO-induced β2-AR signaling was blocked by ICI 118,551, a β2-AR antagonist, in HK-2 cells.RESULTSISO treatment significantly enhanced NHE3 activity, which was reduced by 64.5% with a GRK2 inhibitor (GRK2-IN) and completely inhibited by propranolol (PRO), a non-selective β-adrenergic receptor blocker. Neither GRK2-IN nor PRO impacted NHE3 activity in the absence of ISO. Additionally, while GRK2 expression remained unchanged, ISO markedly decreased ARRB1 expression. This decrease was mitigated by 64.08% with GRK2-IN and entirely blocked by PRO. GRK2-IN and PRO alone did not significantly alter ARRB1 expression.CONCLUSIONOur study suggests that ISO triggers downstream GRK2/ARRB1 signaling to increase NHE3 activity independent of traditional β2AR signaling. Given the fundamental role of NHE3 in renal water-sodium reabsorption, these insights may contribute to new strategies for the prevention and treatment of hypertension.

01 Jul 2025·Cellular Signalling

Paeoniflorin-6’-O-benzene sulfonate inhibits keratinocyte proliferation by restoring GRK2-JAK1 colocalization in mouse model of psoriasis

Article

Author: Guan, Yanling ; Luo, Tingting ; Han, Chenchen ; Wei, Wei ; Tian, Tian ; Ma, Yang ; Wei, Mengzhu ; Rao, Lulu

Psoriasis is chronic inflammatory skin disease mediated by interactions between Th17 cells and keratinocytes that lead to excessive proliferation of keratinocytes, suggesting that anti-inflammatory and anti-proliferation molecules may be effective for the treatment. Paeoniflorin-6'-O-benesulfonic acid (CP-25), an esterified modifier of paeoniflorin, has exhibited potent anti-inflammatory and immunomodulatory properties in arthritis animal models and experimental Sjögren's syndrome. However, the involvement of CP-25 and its target G protein-coupled receptor kinase 2 (GRK2) in the development of psoriasis has not been explored. In this study, we found that GRK2 expression was abnormally elevated in the skin tissues of both psoriasis patients and imiquimod-induced psoriasis model mice. Furthermore, its inhibitor CP-25 reduced skin damage and systemic inflammation in model mice. Mechanically, CP-25 inhibited GRK2 translocation to the cytomembrane, thus decreasing colocalization of GRK2 and the βγ subunit of G protein (Gβγ), increasing colocalization of GRK2 with Janus kinase 1 (JAK1), and downregulating the JAK1-signal transduction and activator of transcription (STAT3) signaling pathway to reduce the hyperproliferation of keratinocytes, besides, CP-25-mediated inhibition of GRK2 translocation to the cytomembrane involved the GRK2 amino acid alanine 321 in keratinocytes. Our findings indicate that targeting GRK2 with CP-25 is a promising treatment for psoriasis.

01 May 2025·Journal of Biological Chemistry

The guanine nucleotide exchange factor Ric-8A regulates the sensitivity of constitutively active Gαq to the inhibitor YM-254890

Article

Author: Blumer, Kendall J ; Dwyer, Morgan B ; Todd, Tyson D ; Wedegaertner, Philip B ; Luo, Jiansong ; Tall, Gregory G

Heterotrimeric G proteins are stimulated under normal circumstances by G protein-coupled receptors to promote downstream intracellular signaling. Mutations can occur in αq at glutamine 209 (Q209) that cause constitutive, G protein-coupled receptor independent signaling due to disruption of GTPase activity. Specifically, Q209L/P mutations are oncogenic drivers of uveal melanoma. YM-254890 (YM) has been shown to selectively inhibit both WT and constitutively active (CA) αqQ209L/P by preventing the release of GDP and exchange for GTP, thereby halting downstream signaling. Because αqQL/P are thought to be primarily GTP-bound and GTPase deficient, the current mechanistic understanding of YM inhibition needs further investigation to clarify how a GDP-dissociation inhibitor could potently inhibit these oncogenic mutants. Here, we expand on the current knowledge of CA αq cellular regulation by demonstrating a direct role for the αq chaperone and guanine nucleotide exchange factor Ric-8A in YM sensitivity. Through signaling assays in RIC-8A KO cells, we found that myristoylated αqQL/P mutants (αqAG-QL/P), previously demonstrated to be YM-resistant, became YM-sensitive, and this was reversed by reintroduction of Ric-8A. Additionally, αqQL demonstrated increased YM sensitivity in the absence of Ric-8A, which was directly altered by the reintroduction of Ric-8A. Pull-down and BRET assays with the RGS-homology domain of GRK2, which can only bind activated αq, further demonstrated that Ric-8A expression enhances activation of αq, its ability to bind effectors, and therefore its ability to signal. With the understanding of YM acting as a GDP-dissociation inhibitor, we propose that Ric-8A hinders YM inhibitory effects by promoting GTP-bound, activated αqQL/P.

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GRK2

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