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Last update 23 Jan 2025

GRK4

Last update 23 Jan 2025

Basic Info

Synonyms

G protein-coupled receptor kinase 2-like (Drosophila), G protein-coupled receptor kinase 4, G protein-coupled receptor kinase GRK4

+ [4]

Introduction

Specifically phosphorylates the activated forms of G protein-coupled receptors. GRK4-alpha can phosphorylate rhodopsin and its activity is inhibited by calmodulin; the other three isoforms do not phosphorylate rhodopsin and do not interact with calmodulin. GRK4-alpha and GRK4-gamma phosphorylate DRD3. Phosphorylates ADRB2.

Drugs associated with GRK4

SM-102 based UNC-GRK4-V mRNA LNP vaccine(University of North Carolina)

Target

GRK4

Mechanism

GRK4 modulators

Active Org.

The University of North Carolina at Chapel Hill

Originator Org.

The University of North Carolina at Chapel Hill

Active Indication

Leukemia

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with GRK4

100 Translational Medicine associated with GRK4

0 Patents (Medical) associated with GRK4

412

Literatures (Medical) associated with GRK4

01 Feb 2025·British Journal of Pharmacology

Slow dissociation kinetics of fentanyls and nitazenes correlates with reduced sensitivity to naloxone reversal at the μ‐opioid receptor

Article

Author: Santiago, Marina ; Alhosan, Norah ; Henderson, Graeme ; Cavallo, Damiana ; Kelly, Eamonn

AbstractBackground and PurposeFentanyls and nitazenes are μ‐opioid receptor agonists responsible for a large number of opioid overdose deaths. Here, we determined the potency, dissociation kinetics and antagonism by naloxone at the μ receptor of several fentanyl and nitazene analogues, compared to morphine and DAMGO.Experimental ApproachIn vitro assays of G protein activation and signalling and arrestin recruitment were performed. AtT20 cells expressing μ receptors were loaded with a membrane potential dye and changes in fluorescence used to determine agonist potency, dissociation kinetics and susceptibility to antagonism by naloxone. BRET experiments were undertaken in HEK293T cells expressing μ receptors to assess Gi protein activation and β‐arrestin 2 recruitment.Key ResultsThe apparent rate of agonist dissociation from the μ receptor varied: morphine, DAMGO, alfentanil and fentanyl dissociated rapidly, whereas isotonitazene, etonitazene, ohmefentanyl and carfentanil dissociated slowly. Slowly dissociating agonists were more resistant to antagonism by naloxone. For carfentanil, the slow apparent rate of dissociation was not because of G protein receptor kinase‐mediated arrestin recruitment as its apparent rate of dissociation was not increased by inhibition of G protein‐coupled receptor kinases (GRKs) with Compound 101. The in vitro relative potencies of fentanyls and nitazenes compared to morphine were much lower than that previously observed in in vivo experiments.Conclusions and ImplicationsWith fentanyls and nitazenes that slowly dissociate from the μ receptor, antagonism by naloxone is pseudo‐competitive. In overdoses involving fentanyls and nitazenes, higher doses of naloxone may be required for reversal than those normally used to reverse heroin overdose.

31 Dec 2024·Clinical and Experimental Hypertension

Chronic exercise improves renal AT ₁ and ETB receptor functions via modulating GRK4 expression in obese Zucker rats

Article

Author: Li, Zhengsheng ; Lu, Jingjing ; Yang, Yinan ; Wei, Fangning

BACKGROUNDPhysical activity has profound benefits on health, especially in patients with cardiovascular and metabolic disease. Exercise training can reduce oxidative stress, improve renal function, and thus lower blood pressure. However, the effect of exercise training on angiotensin II type 1 receptors (AT₁R) and endothelin subtype B receptors (ETBR)-mediated diuresis and natriuresis in obese Zucker rats is unclear.METHODSLean and obese Zucker rats were exercised or placed on a nonmoving treadmill for 8 weeks. Blood pressure was measured by tail-cuff plethysmography, and functions of AT₁R and ETBR in the kidney were measured by natriuresis, respectively.RESULTSOur data showed that exercise training improved glucose and lipid metabolism, renal function and sodium excretion in obese Zucker rats, accompanied by decreased oxidative stress and GRK4 expression in obese Zucker rats. Moreover, exercise training reduced the Candesartan-induced an increase in diuresis and natriuresis and increased ETBR agonists (BQ3020)-mediated diuresis and natriuresis in obese Zucker rats, which were associated with decreased renal AT₁R expression and ETBR phosphorylation levels.CONCLUSIONSThe results demonstrate that exercise training lowers blood pressure via improving renal AT₁R and ETBR function through modulating GRK4 expression in Obese Zucker Rats and provides potentially effective targets for obesity-related hypertension.

22 Nov 2024·Briefings in Bioinformatics

Deciphering the genetic interplay between depression and dysmenorrhea: a Mendelian randomization study

Article

Author: Moraros, John ; Wei, Zhen ; Liu, Shuhe ; Carr, Daniel F

AbstractBackgroundThis study aims to explore the link between depression and dysmenorrhea by using an integrated and innovative approach that combines genomic, transcriptomic, and protein interaction data/information from various resources.MethodsA two-sample, bidirectional, and multivariate Mendelian randomization (MR) approach was applied to determine causality between dysmenorrhea and depression. Genome-wide association study (GWAS) data were used to identify genetic variants associated with both dysmenorrhea and depression, followed by colocalization analysis of shared genetic influences. Expression quantitative trait locus (eQTL) data were analyzed from public databases to pinpoint target genes in relevant tissues. Additionally, a protein–protein interaction (PPI) network was constructed using the STRING database to analyze interactions among identified proteins.ResultsMR analysis confirmed a significant causal effect of depression on dysmenorrhea [‘odds ratio’ (95% confidence interval) = 1.51 (1.19, 1.91), P = 7.26 × 10−4]. Conversely, no evidence was found to support a causal effect of dysmenorrhea on depression (P = .74). Genetic analysis, using GWAS and eQTL data, identified single-nucleotide polymorphisms in several genes, including GRK4, TRAIP, and RNF123, indicating that depression may impact reproductive function through these genetic pathways, with a detailed picture presented by way of analysis in the PPI network. Colocalization analysis highlighted rs34341246(RBMS3) as a potential shared causal variant.ConclusionsThis study suggests that depression significantly affects dysmenorrhea and identifies key genes and proteins involved in this interaction. The findings underline the need for integrated clinical and public health approaches that screen for depression among women presenting with dysmenorrhea and suggest new targeted preventive strategies.

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GRK4

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