RAMP and MRAP accessory proteins have selective effects on expression and signalling of the CB 1 , CB 2 , GPR18 and GPR55 cannabinoid receptors.

Autor: Glenn NAK; Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.; Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand., Finlay DB; Department of Pharmacology and Toxicology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand., Carruthers ER; Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.; Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.; Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand., Mountjoy KG; Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.; Department of Molecular Medicine and Pathology, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.; Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand., Walker CS; Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand.; School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand., Grimsey NL; Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.; Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.; Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2024 Jul; Vol. 181 (14), pp. 2212-2231. Date of Electronic Publication: 2023 Jun 01.
DOI: 10.1111/bph.16095
Abstrakt: Background and Purpose: Receptor activity-modifying proteins (RAMPs) and melanocortin receptor accessory proteins (MRAPs) modulate expression and signalling of calcitonin and melanocortin GPCRs. Interactions with other GPCRs have also been reported. The cannabinoid receptors, CB 1 and CB 2 , and two putative cannabinoid receptors, GPR18 and GPR55, exhibit substantial intracellular expression and there are discrepancies in ligand responsiveness between studies. We investigated whether interactions with RAMPs or MRAPs could explain these phenomena.
Experimental Approach: Receptors and accessory proteins were co-expressed in HEK-293 cells. Selected receptors were studied at basal expression levels and also with enhanced expression produced by incorporation of a preprolactin signal sequence/peptide (pplss). Cell surface and total expression of receptors and accessory proteins were quantified using immunocytochemistry. Signalling was measured using cAMP (CAMYEL) and G protein dissociation (TRUPATH Gα 13 ) biosensors.
Key Results: MRAP2 enhanced surface and total expression of GPR18. Pplss-GPR18 increased detection of cell surface MRAP2. MRAP1α and MRAP2 reduced GPR55 surface and total expression, correlating with reduced constitutive, but not agonist-induced, signalling. GPR55, pplss-CB 1 and CB 2 reduced detection of MRAP1α at the cell surface. Pplss-CB 1 agonist potency was reduced by MRAP2 in Gα 13 but not cAMP assays, consistent with MRAP2 reducing pplss-CB 1 expression. Some cannabinoid receptors increased RAMP2 or RAMP3 total expression without influencing surface expression.
Conclusions and Implications: Mutual influences on expression and/or function for specific accessory protein-receptor pairings raises the strong potential for physiological and disease-relevant consequences. Sequestration and/or hetero-oligomerisation of cannabinoid receptors with accessory proteins is a possible novel mechanism for receptor crosstalk.
Linked Articles: This article is part of a themed issue Therapeutic Targeting of G Protein-Coupled Receptors: hot topics from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists 2021 Virtual Annual Scientific Meeting. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.14/issuetoc.
(© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
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