人组胺 H3 受体亚型的亚型偏差的结构和分子决定因素,ACS Chemical Neuroscience

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人组胺 H3 受体亚型的亚型偏差的结构和分子决定因素
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2023-01-26 , DOI: 10.1021/acschemneuro.2c00425
Sabrina N Rahman _{1,

2} , Daniel A McNaught-Flores ₁ , Yara Huppelschoten ₁ , Daniel da Costa Pereira ₁ , Arthur Christopoulos ₂ , Rob Leurs ₁ , Christopher J Langmead ₂

Affiliation

人类组胺 H ₃受体 (hH ₃ R) 主要在中枢神经系统中表达，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，hH ₃ R 与各种中枢神经系统疾病有关，包括阿尔茨海默病和帕金森病。值得注意的是，hH ₃ R 基因经历了广泛的剪接，产生了 20 种亚型，其中 7TM 亚型在细胞内环 3 (IL3) 和/或 C 末端尾部表现出变异。特别是，显示 IL3 变化的 hH ₃ R 亚型（例如，hH ₃ R-365）显示通过 Gα _{i发出差异信号}-依赖于偏向激动剂（例如，immepip、proxifan、imetit）结合的途径。_{然而，hH 3} R 异构体偏向激动的潜在机制仍然未知。通过对范围广泛的 H _{3 R 激动剂进行结构-功能关系研究，我们由此探索了 hH}₃ R 亚型的亚型偏倚的决定因素，这些亚型在 IL3 中表现出变异（即，hH ₃ R-445、-415、-365 和-329) 在 Gα _i依赖性途径（cAMP 抑制）中。因此，我们系统地描述了 hH ₃通过将各种配体特性（即结构和分子）与异构体偏差程度进行比较，R 异构体对异构体偏差的影响。重要的是，我们的研究提供了对受体亚型偏倚的结构和分子基础的新见解，强调了研究具有多种亚型的 GPCR 以更好地定制药物的重要性。

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Structural and Molecular Determinants for Isoform Bias at Human Histamine H3 Receptor Isoforms

The human histamine H₃ receptor (hH₃R) is predominantly expressed in the CNS, where it regulates the synthesis and release of histamine and other neurotransmitters. Due to its neuromodulatory role, the hH₃R has been associated with various CNS disorders, including Alzheimer’s and Parkinson’s disease. Markedly, the hH₃R 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, hH₃R isoforms that display variations in IL3 (e.g., hH₃R-365) are shown to differentially signal via Gα_i-dependent pathways upon binding of biased agonists (e.g., immepip, proxifan, imetit). Nevertheless, the mechanisms underlying biased agonism at hH₃R isoforms remain unknown. Using a structure–function relationship study with a broad range of H₃R agonists, we thereby explored determinants underlying isoform bias at hH₃R isoforms that exhibit variations in IL3 (i.e., hH₃R-445, -415, -365, and -329) in a Gα_i-dependent pathway (cAMP inhibition). Hence, we systematically characterized hH₃R 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.

更新日期：2023-01-26

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