Amsterdam Institute of Molecular and Life Sciences, Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands.
Biomolecules. 2024 Jun 26;14(7):761. doi: 10.3390/biom14070761.
Alternative splicing significantly enhances the diversity of the G protein-coupled receptor (GPCR) family, including the histamine H receptor (HR). This post-transcriptional modification generates multiple HR isoforms with potentially distinct pharmacological and physiological profiles. HR 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 HR antagonists/inverse agonists, the functional significance of the numerous HR isoforms remains largely enigmatic. Recent publicly available RNA sequencing data have confirmed the expression of multiple HR 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 HR isoforms with a focus on their potential roles in central nervous system (CNS) function. Comparative analysis across species highlights evolutionary conservation and divergence in HR splicing, suggesting species-specific regulatory mechanisms. Understanding the functionality of HR 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.
选择性剪接显著增加了 G 蛋白偶联受体 (GPCR) 家族的多样性，包括组胺 H 受体 (HR)。这种转录后修饰产生了多种 HR 同工型，它们可能具有不同的药理学和生理学特征。HR 主要参与中枢神经系统中神经递质释放的突触前抑制。尽管批准了培哚沙明用于嗜睡症 (Wakix) 和阻塞性睡眠呼吸暂停成人的日间嗜睡 (Ozawade)，并且其他 HR 拮抗剂/反向激动剂的临床试验正在进行中，但众多 HR 同工型的功能意义在很大程度上仍然是个谜。最近公开的 RNA 测序数据证实了多种 HR 同工型在大脑中的表达，其中一些同工型表现出独特的组织特异性分布模式，暗示了同工型特异性功能和神经回路内的相互作用。在这篇综述中，我们讨论了 HR 同工型的复杂性，重点讨论了它们在中枢神经系统 (CNS) 功能中的潜在作用。跨物种的比较分析突出了 HR 剪接的进化保守性和分歧，表明存在物种特异性的调节机制。了解 HR 同工型的功能对于开发靶向治疗至关重要。这一知识将为更精确的药理学干预措施的设计提供信息，从而有可能提高治疗神经和精神疾病的疗效并减少不良反应。
