GPR55 regulates the responsiveness to, but does not dimerise with, α1A-adrenoceptors.

Walsh, Sarah K.; Lipina, Christopher; Ang, Sheng Y.; Sato, Masaaki; Chia, Ling Yeong; Kocan, Martina; Hutchinson, Dana S.; Summers, Roger J.; Wainwright, Cherry L.

Abstract

Emerging evidence suggests that G protein coupled receptor 55 (GPR55) may influence adrenoceptor function/activity in the cardiovascular system. Whether this reflects direct interaction (dimerization) between receptors or signalling crosstalk has not been investigated. This study explored the interaction between GPR55 and the alpha 1A-adrenoceptor (α1A-AR) in the cardiovascular system and the potential to influence function/signalling activities. GPR55 and α1A-AR mediated changes in both cardiac and vascular function was assessed in male wild-type (WT) and GPR55 homozygous knockout (GPR55-/-) mice by pressure volume loop analysis and isolated vessel myography, respectively. Dimerization of GPR55 with the α1A-AR was examined in transfected Chinese hamster ovary-K1 (CHO-K1) cells via Bioluminescence Resonance Energy Transfer (BRET). GPR55 and α1A-AR mediated signalling (extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation) was investigated in neonatal rat ventricular cardiomyocytes using AlphaScreen proximity assays. GPR55-/- mice exhibited both enhanced pressor and inotropic responses to A61603 (α1A-AR agonist), while in isolated vessels, A61603 induced vasoconstriction was attenuated by a GPR55-dependent mechanism. Conversely, GPR55-mediated vasorelaxation was not altered by pharmacological blockade of α1A-ARs with tamsulosin. While cellular studies demonstrated that GPR55 and α1A-AR failed to dimerize, pharmacological blockade of GPR55 altered α1A-AR mediated signalling and reduced ERK1/2 phosphorylation. Taken together, this study provides evidence that GPR55 and α1A-AR do not dimerize to form heteromers, but do interact at the signalling level to modulate the function of α1A-AR in the cardiovascular system.

Citation

WALSH, S.K., LIPINA, C., ANG, S.Y., SATO, M., CHIA, L.Y., KOCAN, M., HUTCHINSON, D.S., SUMMERS, R.J. and WAINWRIGHT, C.L. 2021. GPR55 regulates the responsiveness to, but does not dimerise with, α1A-adrenoceptors. Biochemical pharmacology [online], 188, article ID 114560. Available from: https://doi.org/10.1016/j.bcp.2021.114560

• Journal Article Type: Article
• Acceptance Date: Apr 6, 2021
• Online Publication Date: May 1, 2021
• Publication Date: Jun 30, 2021
• Deposit Date: May 14, 2021
• Publicly Available Date: May 2, 2022
• Journal: Biochemical Pharmacology
• Print ISSN: 0006-2952
• Electronic ISSN: 1873-2968
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 188
• Article Number: 114560
• DOI: https://doi.org/10.1016/j.bcp.2021.114560
• Keywords: GPR55; α1A-adrenoceptor; Cardiac function; Receptor crosstalk
• Public URL: https://rgu-repository.worktribe.com/output/1335100