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.

Keywords: AED; Epilepsy; Epileptogenesis; GPCR; Seizure; cAMP.