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Discovery of a functionally selective ghrelin receptor (GHSR_1a) ligand for modulating brain dopamine.

ABSTRACT: SignificanceThe modulation of growth hormone secretagogue receptor-1a (GHSR_1a) signaling is a promising strategy for treating brain conditions of metabolism, aging, and addiction. GHSR_1a activation results in pleiotropic physiological outcomes through distinct and pharmacologically separable G protein- and β-arrestin (βarr)-dependent signaling pathways. Thus, pathway-selective modulation can enable improved pharmacotherapeutics that can promote therapeutic efficacy while mitigating side effects. Here, we describe the discovery of a brain-penetrant small molecule, N8279 (NCATS-SM8864), that biases GHSR_1a conformations toward Gα_q activation and reduces aberrant dopaminergic behavior in mice. N8279 represents a promising chemical scaffold to advance the development of better treatments for GHSR_1a-related brain disorders involving the pathological dysregulation of dopamine.

SUBMITTER: Gross JD

PROVIDER: S-EPMC8915830 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Discovery of a functionally selective ghrelin receptor (GHSR1a) ligand for modulating brain dopamine.

Gross J D JD Kim D W DW Zhou Y Y Jansen D D Slosky L M LM Clark N B NB Ray C R CR Hu X X Southall N N Wang A A Xu X X Barnaeva E E Wetsel W C WC Ferrer M M Marugan J J JJ Caron M G MG Barak L S LS Toth K K

Proceedings of the National Academy of Sciences of the United States of America 20220303 10

SignificanceThe modulation of growth hormone secretagogue receptor-1a (GHSR1a) signaling is a promising strategy for treating brain conditions of metabolism, aging, and addiction. GHSR1a activation results in pleiotropic physiological outcomes through distinct and pharmacologically separable G protein- and β-arrestin (βarr)-dependent signaling pathways. Thus, pathway-selective modulation can enable improved pharmacotherapeutics that can promote therapeutic efficacy while mi ...[more]

PMID: 35239443

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Project description:Our previous study reported that the DNA methylation of growth hormone secretagogue receptor (GHSR) was significantly higher in thymoma or thymic carcinoma (TC) than in normal thymic tissue samples. Thymic epithelial tumors (TETs) with higher GHSR DNA methylation were associated with significantly worse prognosis than those with lower levels of DNA methylation. Diversified components of the ghrelin-GHSR axis may exert opposing effects in cancer progression, depending on the cancer type in question. However, the precise function of the axis remains unclear. In the present study, the mRNA expression of five key components of the ghrelin system [native ligand ghrelin, variant ligand In-1 ghrelin, native receptor GHSR1a, variant receptor GHSR1b and acylation enzyme ghrelin O-acyltransferase (GOAT)] were examined in 58 TET samples by reverse transcription-quantitative PCR, and protein expression of GHSR1a and GHSR1b was assessed in 20 TETs using immunohistochemistry. The results revealed that In-1 ghrelin, GHSR1b (variant forms) and GOAT were more strongly expressed in thymoma compared with thymic-adjacent tissue. By contrast, no significant differences were observed in the expression of ghrelin and GHSR1a (native forms) between thymoma and thymic tissue. The mRNA expression of In-1 ghrelin and GHSR1b (variant forms) was positively associated with GHSR methylation in thymoma tissue samples. However, a relationship was not found between ghrelin, GHSR1a or GOAT expression (native forms) and GHSR methylation in thymoma. Immunohistochemical analysis revealed that mRNA expression of GHSR1a and GHSR1b generally correlated with expression of the corresponding protein, and that the expression of GHSR1b was increased in advanced-stage TETs. These results indicate that the DNA methylation of GHSR is associated with a shift from native expression (ghrelin and GHSR1a) to variant expression (In-1 ghrelin and GHSR1b), which induces the tumorigenesis of thymoma, but not TC.

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Discovery of a functionally selective ghrelin receptor (GHSR_1a) ligand for modulating brain dopamine.

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Discovery of a functionally selective ghrelin receptor (GHSR<sub>1a</sub>) ligand for modulating brain dopamine.

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Discovery of a functionally selective ghrelin receptor (GHSR1a) ligand for modulating brain dopamine.

Publications

Discovery of a functionally selective ghrelin receptor (GHSR&lt;sub&gt;1a&lt;/sub&gt;) ligand for modulating brain dopamine.

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OmicsDI is part of the ELIXIR infrastructure

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Discovery of a functionally selective ghrelin receptor (GHSR_1a) ligand for modulating brain dopamine.

Discovery of a functionally selective ghrelin receptor (GHSR<sub>1a</sub>) ligand for modulating brain dopamine.