TY - JOUR

T1 - Structural and Molecular Determinants for Isoform Bias at Human Histamine H3 Receptor Isoforms

AU - Rahman, Sabrina N.

AU - McNaught-Flores, Daniel A.

AU - Huppelschoten, Yara

AU - da Costa Pereira, Daniel

AU - Christopoulos, Arthur

AU - Leurs, Rob

AU - Langmead, Christopher J.

N1 - Funding Information: This work was supported by the TOPPUNT [“7 ways to 7TMR modulation (7-to-7)”] [Grant 718.014.002] of The Netherlands Organization for Scientific Research (NWO). Publisher Copyright: © 2023 American Chemical Society.

PY - 2023/2/15

Y1 - 2023/2/15

N2 - 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.

AB - 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.

KW - biased signaling

KW - G protein-coupled receptor (GPCR)

KW - histamine H receptor (hHR)

KW - isoform bias

KW - neuromodulation

KW - structure−activity relationship (SAR)

U2 - 10.1021/acschemneuro.2c00425

DO - 10.1021/acschemneuro.2c00425

M3 - Journal article

C2 - 36702158

AN - SCOPUS:85147153566

VL - 14

SP - 645

EP - 656

JO - ACS Chemical Neuroscience

JF - ACS Chemical Neuroscience

SN - 1948-7193

IS - 4

ER -