GPR39 and GPR40 in epilepsy: a potential therapeutic target for rational drug design, pathophysiology, current understanding and challenges.

G-protein-coupled receptors (GPCRs) are the most abundant family of transmembrane proteins that regulate a variety of physiological functions and are the molecular target of more than 35 % of currently authorised medicines. Recent structural biology advances have significantly improved our understanding of GPCRs activation mechanisms and their interactions with G-protein and β-arrestin signaling pathways, where they regulate neurotransmission at synapses and maintain neuronal homeostasis by activating heterotrimeric G-protein (Gαβγ). Evidence from preclinical studies suggests that GPCRs enhance neuronal excitability, especially in epilepsy, a condition impacting about 1-2% of the global population. Currently approved antiepileptic drugs (AEDs) mainly target ion channels but fail to address key pathological mechanisms such as neuroinflammation, synaptic remodelling, and imbalance in excitatory/inhibitory neurotransmission. These unresolved mechanisms, combined with the side effects of AEDs, present a significant therapeutic gap in seizure treatment and drug-resistant seizures. This gap in therapy highlights the need for ongoing research into novel molecular targets for more effective epilepsy treatments. The keywords GPR39, GPR40, epilepsy, seizure, convulsive, and GPCRs were used to search PubMed, Scopus, and Web of Science. This review explores recent insights into the roles of specific GPCR families in initiating, spreading, or attenuating seizures. It also discusses challenges in developing GPCR-targeted therapies and suggests strategies to overcome these obstacles. A particular focus is placed on GPR39 and GPR40, highlighting their roles in seizure modulation and their potential to prevent epileptogenesis and neuroinflammation. However, more research is necessary to clarify uncertainties regarding how ligand interactions with GPCRs affect physiological and therapeutic outcomes.