Dataset Information

G protein-coupled receptors in acquired epilepsy: Druggability and translatability.

ABSTRACT: As the largest family of membrane proteins in the human genome, G protein-coupled receptors (GPCRs) constitute the targets of more than one-third of all modern medicinal drugs. In the central nervous system (CNS), widely distributed GPCRs in neuronal and nonneuronal cells mediate numerous essential physiological functions via regulating neurotransmission at the synapses. Whereas their abnormalities in expression and activity are involved in various neuropathological processes. CNS conditions thus remain highly represented among the indications of GPCR-targeted agents. Mounting evidence from a large number of animal studies suggests that GPCRs play important roles in the regulation of neuronal excitability associated with epilepsy, a common CNS disease afflicting approximately 1-2% of the population. Surprisingly, none of the US Food and Drug Administration (FDA)-approved (>30) antiepileptic drugs (AEDs) suppresses seizures through acting on GPCRs. This disparity raises concerns about the translatability of these preclinical findings and the druggability of GPCRs for seizure disorders. The currently available AEDs intervene seizures predominantly through targeting ion channels and have considerable limitations, as they often cause unbearable adverse effects, fail to control seizures in over 30% of patients, and merely provide symptomatic relief. Thus, identifying novel molecular targets for epilepsy is highly desired. Herein, we focus on recent progresses in understanding the comprehensive roles of several GPCR families in seizure generation and development of acquired epilepsy. We also dissect current hurdles hindering translational efforts in developing GPCRs as antiepileptic and/or antiepileptogenic targets and discuss the counteracting strategies that might lead to a potential cure for this debilitating CNS condition.

SUBMITTER: Yu Y

PROVIDER: S-EPMC6927250 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Publications

G protein-coupled receptors in acquired epilepsy: Druggability and translatability.

Yu Ying Y Nguyen Davis T DT Jiang Jianxiong J

Progress in neurobiology 20190824

As the largest family of membrane proteins in the human genome, G protein-coupled receptors (GPCRs) constitute the targets of more than one-third of all modern medicinal drugs. In the central nervous system (CNS), widely distributed GPCRs in neuronal and nonneuronal cells mediate numerous essential physiological functions via regulating neurotransmission at the synapses. Whereas their abnormalities in expression and activity are involved in various neuropathological processes. CNS conditions thu ...[more]

PMID: 31454545

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Project description:The years 2000 and 2007 witnessed milestones in current understanding of G protein-coupled receptor (GPCR) structural biology. In 2000 the first GPCR, bovine rhodopsin, was crystallized and the structure was solved, while in 2007 the structure of ?(2)-adrenergic receptor, the first GPCR with diffusible ligands, was determined owing to advances in microcrystallization and an insertion of the fast-folding lysozyme into the receptor. In parallel with those crystallographic studies, the biological and biochemical characterization of GPCRs has advanced considerably because those receptors are molecular targets for many of currently used drugs. Therefore, the mechanisms of activation and signal transduction to the cell interior deduced from known GPCRs structures are of the highest importance for drug discovery. These proteins are the most diversified membrane receptors encoded by hundreds of genes in our genome. They participate in processes responsible for vision, smell, taste and neuronal transmission in response to photons or binding of ions, hormones, peptides, chemokines and other factors. Although the GPCRs share a common seven-transmembrane ?-helical bundle structure their binding sites can accommodate thousands of different ligands. The ligands, including agonists, antagonists or inverse agonists change the structure of the receptor. With bound agonists they can form a complex with a suitable G protein, be phosphorylated by kinases or bind arrestin. The discovered signaling cascades invoked by arrestin independently of G proteins makes the GPCR activating scheme more complex such that a ligand acting as an antagonist for G protein signaling can also act as an agonist in arrestin-dependent signaling. Additionally, the existence of multiple ligand-dependent partial activation states as well as dimerization of GPCRs result in a 'microprocessor-like' action of these receptors rather than an 'on-off' switch as was commonly believed only a decade ago.

Dataset Information

G protein-coupled receptors in acquired epilepsy: Druggability and translatability.

Publications

G protein-coupled receptors in acquired epilepsy: Druggability and translatability.

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