Drug Discovery Biology and Neuromedicines Discovery Centre, Monash Institute of Pharmaceutical Sciences, Monash University, 399 Royal Parade, 3052 VIC, Parkville, Melbourne, Australia; Amsterdam Institute for Molecular Life Sciences, Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.
Amsterdam Institute for Molecular Life Sciences, Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.
Biochem Pharmacol. 2024 Oct;228:115988. doi: 10.1016/j.bcp.2023.115988. Epub 2023 Dec 28.
The histamine H receptor (HR) is a neurotransmitter receptor that is primarily found in the brain, where it controls the release and synthesis of histamine, as well as the release of other neurotransmitters (e.g. dopamine, serotonin). Notably, 20 HR isoforms are differentially expressed in the human brain as a consequence of alternative gene splicing. The hHR-445, -415, -365 and -329 isoforms contain the prototypical GPCR (7TM) structure, yet exhibit deletions in the third intracellular loop, a structural domain that is pivotal for G protein-coupling, signaling and regulation. To date, the physiological relevance underlying the individual and combinatorial function of hHR isoforms remains poorly understood. Nevertheless, given their significant implication in physiological processes (e.g. cognition, homeostasis) and neurological disorders (e.g. Alzheimer's and Parkinson's disease, schizophrenia), widespread targeting of hHR isoforms by drugs may lead to on-target side effects in brain regions that are unaffected by disease. To this end, isoform- and/or pathway-selective targeting of hHR isoforms by biased agonists could be of therapeutic relevance for the development of region- and disease-specific drugs. Hence, we have evaluated ligand biased signaling at the hHR-445, -415, -365 and -329 isoforms across various Gα-mediated (i.e. [S]GTPγS accumulation, cAMP inhibition, pERK1/2 activation, pAKT T308/S473 activation) and non Gα-mediated (i.e. β-arrestin2 recruitment) endpoints that are relevant to neurological diseases. Our findings indicate that HR agonists display significantly altered patterns in their degree of ligand bias, in a pathway- and isoform-dependent manner, underlining the significance to investigate GPCRs with multiple isoforms to improve development of selective drugs. SUBJECT CATEGORY: Neuropharmacology.
组胺 H 受体（HR）是一种神经递质受体，主要存在于大脑中，它控制组胺的释放和合成，以及其他神经递质（如多巴胺、血清素）的释放。值得注意的是，由于基因剪接的差异，人类大脑中存在 20 种不同的 HR 同工型。hHR-445、-415、-365 和 -329 同工型含有典型的 G 蛋白偶联受体（7TM）结构，但在第三细胞内环中缺失，该结构域对于 G 蛋白偶联、信号转导和调节至关重要。迄今为止，hHR 同工型的个体和组合功能的生理相关性仍知之甚少。然而，鉴于它们在生理过程（如认知、内稳态）和神经疾病（如阿尔茨海默病和帕金森病、精神分裂症）中具有重要意义，药物对 hHR 同工型的广泛靶向可能导致大脑区域出现与疾病无关的靶标副作用。为此，通过偏向激动剂对 hHR 同工型进行同工型和/或途径选择性靶向，可能对开发针对特定区域和疾病的药物具有治疗意义。因此，我们评估了 hHR-445、-415、-365 和 -329 同工型在各种 Gα 介导的（即[S]GTPγS 积累、cAMP 抑制、pERK1/2 激活、pAKT T308/S473 激活）和非 Gα 介导的（即β-arrestin2 募集）终点的配体偏向信号，这些终点与神经疾病相关。我们的研究结果表明，HR 激动剂以途径和同工型依赖的方式显示出配体偏向性程度的显著改变，这突显了研究具有多种同工型的 GPCR 的重要性，以提高选择性药物的开发。主题类别：神经药理学。
