Alternative splicing fuels the functional diversity of GPCR in neurological and psychiatric disorders: An emerging path toward RNA-targeted neurotherapeutics.

Dysfunction in intricate neural circuits contributes to numerous neurological and psychiatric disorders, affecting a substantial portion of the global population and significantly contributing to the global disease burden. This highlights the urgent need for more precise therapeutic targets. G protein-coupled receptors (GPCRs) are the predominant targets commonly utilized in the development of novel therapeutics for nervous system disorders. Alternative splicing (AS) generates numerous tissue- and cell type-specific GPCR isoforms that are regulated by cis-acting elements, trans-acting factors, and underlying epigenetic modifications. These isoforms exhibit distinct distributions, leading to signaling bias and conformational diversity. However, their role in GPCR signaling heterogeneity is often overlooked due to limited data on expression and function in various neuropathological conditions. This review examines GPCR splicing variants (SVs) in neurodegenerative diseases such as Alzheimer's and Parkinson's, neuropsychiatric disorders including depression, anxiety, autism spectrum disorder, and schizophrenia, as well as pain and addiction. It emphasizes how alternative splicing shapes tissue-specific GPCR expression and diverse biological functions. Emerging technologies and AI-based structural modeling are underscored as powerful tools for resolving GPCR variant structures and enabling isoform-specific drug development. The review aims to provide new insights into GPCR functional heterogeneity and promote an isoform-focused therapeutic strategy based on GPCR-ligand interactions to guide future treatments.