Structural and Molecular Determinants for Isoform Bias at Human Histamine H 3 Receptor Isoforms

作者：Sabrina N. Rahman, Daniel A. McNaught-Flores, Yara Huppelschoten, Daniel Da Costa Pereira, Arthur Christopoulos, Rob Leurs, Christopher J. Langmead · 发表于：ACS Chemical Neuroscience · 年份：2023 · DOI：10.1021/acschemneuro.2c00425 · 被引用次数：9 · 研究领域：Mast cells and histamine、Receptor Mechanisms and Signaling、Asthma and respiratory diseases

The human histamine H 3 receptor (hH 3 R) is predominantly expressed in the CNS, where it regulates the synthesis and release of histamine and other neurotransmitters. Due to its neuromodulatory role, the hH 3 R has been associated with various CNS disorders, including Alzheimer’s and Parkinson’s disease. Markedly, the hH 3 R 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, hH 3 R isoforms that display variations in IL3 (e.g., hH 3 R-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 hH 3 R isoforms remain unknown. Using a structure–function relationship study with a broad range of H 3 R agonists, we thereby explored determinants underlying isoform bias at hH 3 R isoforms that exhibit variations in IL3 (i.e., hH 3 R-445, -415, -365, and -329) in a Gα i -dependent pathway (cAMP inhibition). Hence, we systematically characterized hH 3 R 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.