Histamine H 3 Receptor Isoforms: Insights from Alternative Splicing to Functional Complexity.

Alternative splicing significantly enhances the diversity of the G protein-coupled receptor (GPCR) family, including the histamine H 3 receptor (H 3 R). This post-transcriptional modification generates multiple H 3 R isoforms with potentially distinct pharmacological and physiological profiles. H 3 R is primarily involved in the presynaptic inhibition of neurotransmitter release in the central nervous system. Despite the approval of pitolisant for narcolepsy (Wakix ® ) and daytime sleepiness in adults with obstructive sleep apnea (Ozawade ® ) and ongoing clinical trials for other H 3 R antagonists/inverse agonists, the functional significance of the numerous H 3 R isoforms remains largely enigmatic. Recent publicly available RNA sequencing data have confirmed the expression of multiple H 3 R isoforms in the brain, with some isoforms exhibiting unique tissue-specific distribution patterns hinting at isoform-specific functions and interactions within neural circuits. In this review, we discuss the complexity of H 3 R isoforms with a focus on their potential roles in central nervous system (CNS) function. Comparative analysis across species highlights evolutionary conservation and divergence in H 3 R splicing, suggesting species-specific regulatory mechanisms. Understanding the functionality of H 3 R isoforms is crucial for the development of targeted therapeutics. This knowledge will inform the design of more precise pharmacological interventions, potentially enhancing therapeutic efficacy and reducing adverse effects in the treatment of neurological and psychiatric disorders.