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GPR55 regulates the responsiveness to, but does not dimerise with, ?1A-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.

Authors

Christopher Lipina

Sheng Y. Ang

Masaaki Sato

Ling Yeong Chia

Martina Kocan

Dana S. Hutchinson

Roger J. Summers



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 (?1A-AR) in the cardiovascular system and the potential to influence function/signalling activities. GPR55 and ?1A-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 ?1A-AR was examined in transfected Chinese hamster ovary-K1 (CHO-K1) cells via Bioluminescence Resonance Energy Transfer (BRET). GPR55 and ?1A-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 (?1A-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 ?1A-ARs with tamsulosin. While cellular studies demonstrated that GPR55 and ?1A-AR failed to dimerize, pharmacological blockade of GPR55 altered ?1A-AR mediated signalling and reduced ERK1/2 phosphorylation. Taken together, this study provides evidence that GPR55 and ?1A-AR do not dimerize to form heteromers, but do interact at the signalling level to modulate the function of ?1A-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, ?1A-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; ?1A-adrenoceptor; Cardiac function; Receptor crosstalk
Public URL https://rgu-repository.worktribe.com/output/1335100

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