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The role of GPR56/ADGRG1 in health and disease.

ABSTRACT: GPR56/ADGRG1 is a versatile adhesion G protein-coupled receptor important in the physiological functions of the central and peripheral nervous systems, reproductive system, muscle hypertrophy, immune regulation, and hematopoietic stem cell generation. By contrast, aberrant expression or deregulated functions of GPR56 have been implicated in diverse pathological processes, including bilateral frontoparietal polymicrogyria, depression, and tumorigenesis. In this review article, we summarize and discuss the current understandings of the role of GPR56 in health and disease.

SUBMITTER: Singh AK

PROVIDER: S-EPMC8640549 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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The role of GPR56/ADGRG1 in health and disease.

Singh Abhishek Kumar AK Lin Hsi-Hsien HH

Biomedical journal 20210504 5

GPR56/ADGRG1 is a versatile adhesion G protein-coupled receptor important in the physiological functions of the central and peripheral nervous systems, reproductive system, muscle hypertrophy, immune regulation, and hematopoietic stem cell generation. By contrast, aberrant expression or deregulated functions of GPR56 have been implicated in diverse pathological processes, including bilateral frontoparietal polymicrogyria, depression, and tumorigenesis. In this review article, we summarize and di ...[more]

PMID: 34654683

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Project description:GPR56 is a widely expressed adhesion GPCR (AGPCR) that has pleotropic roles in brain development, platelet function, cancer, and more. Nearly all AGPCRs possess extracellular regions that bind protein ligands and conceal a cryptic tethered peptide agonist. AGPCR reception of mechanical or shear force is thought to release the tethered agonist permitting its binding to the AGPCR orthosteric site for consequent activation of G protein signaling. This multistep mechanism of AGPCR activation is difficult to target, emphasizing the need for tool compounds and potential therapeutics that modulate AGPCRs directly. We expanded our cell-based pilot screen for GPR56 small molecule activators to screen >200,000 compounds and identified two promising agonists: 2-(furan-2-yl)-1-[(4-phenylphenyl)carbonyl]pyrrolidine, or compound 4, and propan-2-yl-4-(2-bromophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate, or compound 36. Both compounds activated GPR56 receptors enginered to have impaired tethered agonists and/or be cleavage deficient. Compound 4 activated a subset of group VIII AGPCRs while compound 36 had exclusive specificity for GPR56 among the GPCRs tested. Compound 36 SAR analysis identified an analog with the isopropyl R group replaced with a cyclopentyl ring and the electrophilic bromine replaced with a CF3 group. Analog 36.40 had 40% increased potency over compound 36 and was 20-fold more potent than synthetic peptidomimetics designed from the GPR56 tethered agonist. The new GPCR56 tool compounds discovered in this screen may be used to further advance understanding of GPR56 function and aid development of AGPCR-targeted therapeutics. SIGNIFICANCE STATEMENT: Adhesion G protein coupled receptors (AGPCRs) are a large, clinically relevant class of GPCRs with no available therapeutics, in part due to their unique mechanism of activation. GPR56 is a widely expressed model AGPCR involved in cancer metastasis, hemostasis, and neuron myelination. In the present study, we identified novel small molecule agonists for GPR56. These molecules are among the most potent identified thus far and may become useful leads in the development of a GPR56-targeted therapeutic.

Dataset Information

The role of GPR56/ADGRG1 in health and disease.

Publications

The role of GPR56/ADGRG1 in health and disease.

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