Ligand-directed biased agonism at human histamine H 3 receptor isoforms across Gα i/o - and β-arrestin2-mediated pathways.

Autor: Rahman SN; Drug Discovery Biology and Neuromedicines Discovery Centre, Monash Institute of Pharmaceutical Sciences, Monash University, 399 Royal Parade, 3052 VIC, Parkville, Melbourne, Australia; Amsterdam Institute for Molecular Life Sciences, Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands. Electronic address: sabrina.rahman@sund.ku.dk., Imhaouran F; Amsterdam Institute for Molecular Life Sciences, Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands., Leurs R; Amsterdam Institute for Molecular Life Sciences, Division of Medicinal Chemistry, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands., Christopoulos A; Drug Discovery Biology and Neuromedicines Discovery Centre, Monash Institute of Pharmaceutical Sciences, Monash University, 399 Royal Parade, 3052 VIC, Parkville, Melbourne, Australia., Valant C; Drug Discovery Biology and Neuromedicines Discovery Centre, Monash Institute of Pharmaceutical Sciences, Monash University, 399 Royal Parade, 3052 VIC, Parkville, Melbourne, Australia. Electronic address: celine.valant@monash.edu., Langmead CJ; Drug Discovery Biology and Neuromedicines Discovery Centre, Monash Institute of Pharmaceutical Sciences, Monash University, 399 Royal Parade, 3052 VIC, Parkville, Melbourne, Australia. Electronic address: chris.langmead@monash.edu.
Jazyk: angličtina
Zdroj: Biochemical pharmacology [Biochem Pharmacol] 2024 Oct; Vol. 228, pp. 115988. Date of Electronic Publication: 2023 Dec 28.
DOI: 10.1016/j.bcp.2023.115988
Abstrakt: The histamine H 3 receptor (H 3 R) is a neurotransmitter receptor that is primarily found in the brain, where it controls the release and synthesis of histamine, as well as the release of other neurotransmitters (e.g. dopamine, serotonin). Notably, 20 H 3 R isoforms are differentially expressed in the human brain as a consequence of alternative gene splicing. The hH 3 R-445, -415, -365 and -329 isoforms contain the prototypical GPCR (7TM) structure, yet exhibit deletions in the third intracellular loop, a structural domain that is pivotal for G protein-coupling, signaling and regulation. To date, the physiological relevance underlying the individual and combinatorial function of hH 3 R isoforms remains poorly understood. Nevertheless, given their significant implication in physiological processes (e.g. cognition, homeostasis) and neurological disorders (e.g. Alzheimer's and Parkinson's disease, schizophrenia), widespread targeting of hH 3 R isoforms by drugs may lead to on-target side effects in brain regions that are unaffected by disease. To this end, isoform- and/or pathway-selective targeting of hH 3 R isoforms by biased agonists could be of therapeutic relevance for the development of region- and disease-specific drugs. Hence, we have evaluated ligand biased signaling at the hH 3 R-445, -415, -365 and -329 isoforms across various Gα i/o -mediated (i.e. [ 35 S]GTPγS accumulation, cAMP inhibition, pERK1/2 activation, pAKT T308/S473 activation) and non Gα i/o -mediated (i.e. β-arrestin2 recruitment) endpoints that are relevant to neurological diseases. Our findings indicate that H 3 R agonists display significantly altered patterns in their degree of ligand bias, in a pathway- and isoform-dependent manner, underlining the significance to investigate GPCRs with multiple isoforms to improve development of selective drugs. SUBJECT CATEGORY: Neuropharmacology.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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