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Function and therapeutic potential of G protein-coupled receptors in epididymis.

ABSTRACT: Infertility rates for both females and males have increased continuously in recent years. Currently, effective treatments for male infertility with defined mechanisms or targets are still lacking. G protein-coupled receptors (GPCRs) are the largest class of drug targets, but their functions and the implications for the therapeutic development for male infertility largely remain elusive. Nevertheless, recent studies have shown that several members of the GPCR superfamily play crucial roles in the maintenance of ion-water homeostasis of the epididymis, development of the efferent ductules, formation of the blood-epididymal barrier and maturation of sperm. Knowledge of the functions, genetic variations and working mechanisms of such GPCRs, along with the drugs and ligands relevant to their specific functions, provide future directions and a great arsenal for new developments in the treatment of male infertility.

SUBMITTER: Zhang D

PROVIDER: S-EPMC7707088 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Function and therapeutic potential of G protein-coupled receptors in epididymis.

Zhang Daolai D Wang Yanfei Y Lin Hui H Sun Yujing Y Wang Mingwei M Jia Yingli Y Yu Xiao X Jiang Hui H Xu Wenming W Sun Jin-Peng JP Xu Zhigang Z

British journal of pharmacology 20201029 24

Infertility rates for both females and males have increased continuously in recent years. Currently, effective treatments for male infertility with defined mechanisms or targets are still lacking. G protein-coupled receptors (GPCRs) are the largest class of drug targets, but their functions and the implications for the therapeutic development for male infertility largely remain elusive. Nevertheless, recent studies have shown that several members of the GPCR superfamily play crucial roles in the ...[more]

PMID: 32901914

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Project description:Alzheimer's disease (AD), particularly its sporadic or late-onset form (SAD/LOAD), is the most prevalent (96-98% of cases) neurodegenerative dementia in aged people. AD's neuropathology hallmarks are intrabrain accumulation of amyloid-? peptides (A?s) and of hyperphosphorylated Tau (p-Tau) proteins, diffuse neuroinflammation, and progressive death of neurons and oligodendrocytes. Mounting evidences suggest that family C G-protein-coupled receptors (GPCRs), which include ?-aminobutyric acid B receptors (GABABRs), metabotropic glutamate receptors (mGluR1-8), and the calcium-sensing receptor (CaSR), are involved in many neurotransmitter systems that dysfunction in AD. This review updates the available knowledge about the roles of GPCRs, particularly but not exclusively those expressed by brain astrocytes, in SAD/LOAD onset and progression, taking stock of their respective mechanisms of action and of their potential as anti-AD therapeutic targets. In particular, GABABRs prevent A?s synthesis and neuronal hyperexcitability and group I mGluRs play important pathogenetic roles in transgenic AD-model animals. Moreover, the specific binding of A?s to the CaSRs of human cortical astrocytes and neurons cultured in vitro engenders a pathological signaling that crucially promotes the surplus synthesis and release of A?s and hyperphosphorylated Tau proteins, and also of nitric oxide, vascular endothelial growth factor-A, and proinflammatory agents. Concurrently, A?s•CaSR signaling hinders the release of soluble (s)APP-? peptide, a neurotrophic agent and GABABR1a agonist. Altogether these effects progressively kill human cortical neurons in vitro and likely also in vivo. Several CaSR's negative allosteric modulators suppress all the noxious effects elicited by A?s•CaSR signaling in human cortical astrocytes and neurons thus safeguarding neurons' viability in vitro and raising hopes about their potential therapeutic benefits in AD patients. Further basic and clinical investigations on these hot topics are needed taking always heed that activation of the several brain family C GPCRs may elicit divergent upshots according to the models studied.

Dataset Information

Function and therapeutic potential of G protein-coupled receptors in epididymis.

Publications

Function and therapeutic potential of G protein-coupled receptors in epididymis.

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