Amsterdam Institute for Molecular Life Sciences, Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZAmsterdam, The Netherlands.
Drug Discovery Biology and Neuromedicines Discovery Centre, Monash Institute of Pharmaceutical Sciences, Monash University, 399 Royal Parade, Parkville, Melbourne, 3052VIC, Australia.
ACS Chem Neurosci. 2023 Feb 15;14(4):645-656. doi: 10.1021/acschemneuro.2c00425. Epub 2023 Jan 26.
The human histamine H receptor (hHR) is predominantly expressed in the CNS, where it regulates the synthesis and release of histamine and other neurotransmitters. Due to its neuromodulatory role, the hHR has been associated with various CNS disorders, including Alzheimer's and Parkinson's disease. Markedly, the hHR gene undergoes extensive splicing, resulting in 20 isoforms, of which 7TM isoforms exhibit variations in the intracellular loop 3 (IL3) and/or C-terminal tail. Particularly, hHR isoforms that display variations in IL3 (e.g., hHR-365) are shown to differentially signal via Gα-dependent pathways upon binding of biased agonists (e.g., immepip, proxifan, imetit). Nevertheless, the mechanisms underlying biased agonism at hHR isoforms remain unknown. Using a structure-function relationship study with a broad range of HR agonists, we thereby explored determinants underlying isoform bias at hHR isoforms that exhibit variations in IL3 (i.e., hHR-445, -415, -365, and -329) in a Gα-dependent pathway (cAMP inhibition). Hence, we systematically characterized hHR isoforms on isoform bias by comparing various ligand properties (i.e., structural and molecular) to the degree of isoform bias. Importantly, our study provides novel insights into the structural and molecular basis of receptor isoform bias, highlighting the importance to study GPCRs with multiple isoforms to better tailor drugs.
人类组胺 H 受体 (hHR) 主要在中枢神经系统 (CNS) 中表达，在那里它调节组胺和其他神经递质的合成和释放。由于其神经调节作用，hHR 与各种 CNS 疾病有关，包括阿尔茨海默病和帕金森病。值得注意的是，hHR 基因经历广泛的剪接，导致 20 种异构体，其中 7TM 异构体在细胞内环 3 (IL3) 和/或 C 末端尾部存在差异。特别是，在结合偏向激动剂（例如 immepip、proxifan、imitet）时，显示 IL3 变化的 hHR 异构体（例如 hHR-365）通过 Gα 依赖性途径表现出不同的信号传导。然而，hHR 异构体偏向激动作用的机制尚不清楚。使用与广泛的 HR 激动剂的结构-功能关系研究，我们因此探索了在 IL3 变化的 hHR 异构体（即 hHR-445、-415、-365 和-329）中表现出偏向激动作用的 Gα 依赖性途径（cAMP 抑制）的异构体偏向的决定因素。因此，我们通过将各种配体性质（即结构和分子）与异构体偏向程度进行比较，系统地对异构体偏向的 hHR 异构体进行了特征描述。重要的是，我们的研究为受体异构体偏向的结构和分子基础提供了新的见解，强调了研究具有多种异构体的 GPCR 以更好地定制药物的重要性。
