Last update 01 Nov 2024

GRK6

Last update 01 Nov 2024

Basic Info

Synonyms

G protein-coupled receptor kinase 6, G protein-coupled receptor kinase GRK6, GPRK6

+ [1]

Introduction

Specifically phosphorylates the activated forms of G protein-coupled receptors. Such receptor phosphorylation initiates beta-arrestin-mediated receptor desensitization, internalization, and signaling events leading to their desensitization. Seems to be involved in the desensitization of D2-like dopamine receptors in striatum and chemokine receptor CXCR4 which is critical for CXCL12-induced cell chemotaxis (By similarity). Phosphorylates rhodopsin (RHO) (in vitro) and a non G-protein-coupled receptor: LRP6 during Wnt signaling (in vitro).

Drugs associated with GRK6

Novel GRK5/6 inhibitors (Purdue University)

Target

GRK5 x GRK6

Mechanism

GRK5 inhibitors [+1]

Active Org.

Purdue University

Originator Org.

Purdue University

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

GF-109203X

Target

GRK6 x PKC

Mechanism

GRK6 antagonists [+1]

Active Org.-

Originator Org.

Pfizer Inc.

Active Indication-

Inactive Indication

Inflammation [+2]

Drug Highest PhasePending

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with GRK6

100 Translational Medicine associated with GRK6

0 Patents (Medical) associated with GRK6

262

Literatures (Medical) associated with GRK6

31 Oct 2024·The FASEB Journal

The role of polo‐like kinases 2 in the proteasomal and lysosomal degradation of alpha‐synuclein in neurons

Article

Author: Sung, Chun Chau ; Lam, Wai Yun ; Chung, Kenny K. K.

AbstractParkinson's disease (PD) is a neurodegenerative disorder caused by the degeneration of dopaminergic neurons in the brain stem. PD is mostly sporadic, but familial PD (FPD) cases are recorded in different studies. The first gene mutation that is linked to FPD is α‐synuclein (α‐syn). It was then found that α‐syn is also accumulated in Lewy body (LB), a classical pathological hallmark in PD patients. Different studies have shown that α‐syn accumulation and aggregation can be a crucial factor contributing to the degeneration of dopaminergic neurons in PD. α‐syn has been found to be degraded by the ubiquitin proteasomal system (UPS) and autophagy–lysosomal pathway (ALP). In this study, we initially explored how α‐syn phosphorylation by GRK6, PLK2 and CK2α would facilitate its degradation in relation to the UPS or ALP. Unexpectedly, we found that the degradation of α‐syn through PLK2 phosphorylation could be modulated by UPS and ALP in a novel mechanism. Specially, attenuation of UPS could increase the amount of PLK2 and then could facilitate the phosphorylation and degradation of α‐syn through ALP. To test this further in vivo, we attenuate the proteasomal activity in a well‐established A53T α‐syn transgenic PD mouse model. We found that attenuation of proteasomal activity in the A53T α‐syn transgenic mice could reduce the accumulation of α‐syn in the striatum and midbrain. Based on our results, this study provides a new insight into how α‐syn is degraded through the UPS and ALP.

07 Jul 2024·Zhonghua er bi yan hou tou jing wai ke za zhi = Chinese journal of otorhinolaryngology head and neck surgery

[Screening and validation of therapeutic targets for chronic sinusitis with nasal polyps based on proteomics].

Article

Author: Li, T ; Song, Z Y ; Sun, C Y ; Zhang, Y ; Yang, Y J ; Song, X C

Objective: To identify potential therapeutic targets of chronic sinusitis with nasal polyps (CRSwNP) through proteomics screening of and verify its effectiveness experimentally. Methods: The nasal tissue samples were collected from patients undergoing surgical treatment in the Department of Otorhinolaryngology, Head and Neck Surgery in Yuhuangding Hospital of Yantai from June 2010 to December 2021, including 69 patients with CRSwNP and 39 patients in the control group. Tissue samples were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) in data-independent acquisition (DIA) mode to find differentially expressed proteins. Bioinformatics tools were employed to analyze the functions of differentially expressed proteins. The expression of hematopoietic cell kinase (HCK) in nasal tissues of patients with CRSwNP was further confirmed by qPCR and western blot. The mouse model of CRSwNP was established and treated with HCK inhibitor. The levels of inflammatory factors IgE, IL-4 and IL-5 in serum of CRSwNP mice, both treated and untreated with HCK inhibitors, were detected by enzyme-linked immunosorbent assay (ELISA) across different experimental groups. The experimental data were analyzed by Graphpad Prism 9 software. Results: DIA analysis identified 1 850 differential proteins, including 760 up-regulated proteins and 1 090 down-regulated proteins. Weighted correlation network analysis (WGCNA) correlation analysis of phenotypic data such as cell count and CT score with the results of genomics indemnified 575 proteins of MEBrown module which intersected with 35 kinases further screened from 1 850 differential proteins, yielding eight protein kinases: HCK, SYK, PDK2, FGR, PRKCB, ROR1, CAMK1 and GRK6. qPCR showed that the expression of HCK in CRSwNP was significantly higher than that in the control group (P<0.05). Further experiments in mice confirmed that the secretion of IgE, IL-4 and IL-5 in the serum of CRSwNP group was significantly higher than the control group (all P<0.05), indicating successful model establishment. The intervention of HCK significantly decreased the secretion of IgE, IL-4 and IL-5 in serum of mice (all P<0.05). Conclusion: The HCK inhibitor can reduce the inflammatory index of mice with CRSwNP, and HCK is a potential therapeutic target of CRSwNP.

01 Jun 2024·iScience

Robust GRK2/3/6-dependent desensitization of oxytocin receptor in neurons

Article

Author: Ahmad, Mohiuddin ; Nagaraja, Raghavendra Y ; Hoang, Hanh T M ; George, Kiran ; Tibbs, Taryn ; Li, Guangpu ; Troyano-Rodriguez, Eva

Oxytocin plays critical roles in the brain as a neuromodulator, regulating social and other affective behavior. However, the regulatory mechanisms controlling oxytocin receptor (OXTR) signaling in neurons remain unexplored. In this study, we have identified robust and rapid-onset desensitization of OXTR response in multiple regions of the mouse brain. Both cell autonomous spiking response and presynaptic activation undergo similar agonist-induced desensitization. G-protein-coupled receptor kinases (GRK) GRK2, GRK3, and GRK6 are recruited to the activated OXTR in neurons, followed by recruitment of β-arrestin-1 and -2. Neuronal OXTR desensitization was impaired by suppression of GRK2/3/6 kinase activity but remained unaltered with double knockout of β-arrestin-1 and -2. Additionally, we observed robust agonist-induced internalization of neuronal OXTR and its Rab5-dependent recruitment to early endosomes, which was impaired by GRK2/3/6 inhibition. This work defines distinctive aspects of the mechanisms governing OXTR desensitization and internalization in neurons compared to prior studies in heterologous cells.

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GRK6

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