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

Sabrina N. Rahman, Daniel A. McNaught-Flores, Yara Huppelschoten, Daniel da Costa Pereira, Arthur Christopoulos, Rob Leurs, Christopher J. Langmead

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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 Gαi-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 Gαi-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.

Original languageEnglish
Pages (from-to)645-656
Number of pages12
JournalACS Chemical Neuroscience
Issue number4
Publication statusPublished - 26 Jan 2023


  • biased signaling
  • G protein-coupled receptor (GPCR)
  • histamine H receptor (hHR)
  • isoform bias
  • neuromodulation
  • structure−activity relationship (SAR)

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