Differential regulation of β2-adrenoceptor and adenosine A2B receptor signalling by GRK and arrestin proteins in arterial smooth muscle

Nash, C.A., Nelson, C.P. ORCID: 0000-0003-1034-140X, Mistry, R., Moeller-Olsen, C., Christofidou, E., Challiss, R.A.J. and Willets, J.M., 2018. Differential regulation of β2-adrenoceptor and adenosine A2B receptor signalling by GRK and arrestin proteins in arterial smooth muscle. Cellular Signalling, 51, pp. 86-98. ISSN 0898-6568

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Abstract

Generation of cAMP through Gs-coupled G protein-coupled receptor (GPCR) [e.g. β2-adrenoceptor (β2AR), adenosine A2B receptor (A2BR)] activation, induces arterial smooth muscle relaxation, counteracting the actions of vasoconstrictors. Gs-coupled GPCR signalling is regulated by G protein-coupled receptor kinases (GRK) and arrestin proteins, and dysregulation of Gs/GPCR signalling is thought play a role in the development of hypertension, which may be a consequence of enhanced GRK2 and/or arrestin expression. However, despite numerous studies indicating that β2AR and A2BR can be substrates for GRK/arrestin proteins, currently little is known regarding GRK/arrestin regulation of these endogenous receptors in arterial smooth muscle. Here, endogenous GRK isoenzymes and arrestin proteins were selectively depleted using RNA-interference in rat arterial smooth muscle cells (RASM) and the consequences of this for β2AR- and A2BR-mediated adenylyl cyclase (AC) signalling were determined by assessing cAMP accumulation. GRK2 or GRK5 depletion enhanced and prolonged β2AR/AC signalling, while combined deletion of GRK2/5 has an additive effect. Conversely, activation of AC by A2BR was regulated by GRK5, but not GRK2. β2AR desensitization was attenuated following combined GRK2/GRK5 knockdown, but not by depletion of individual GRKs, arrestins, or by inhibiting PKA. Arrestin3 (but not arrestin2) depletion enhanced A2BR-AC signalling and attenuated A2BR desensitization, while β2AR-AC signalling was regulated by both arrestin isoforms. This study provides a first demonstration of how different complements of GRK and arrestin proteins contribute to the regulation of signalling and desensitization of these important receptors mediating vasodilator responses in arterial smooth muscle.

Item Type: Journal article
Publication Title: Cellular Signalling
Creators: Nash, C.A., Nelson, C.P., Mistry, R., Moeller-Olsen, C., Christofidou, E., Challiss, R.A.J. and Willets, J.M.
Publisher: Elsevier
Date: November 2018
Volume: 51
ISSN: 0898-6568
Identifiers:
NumberType
10.1016/j.cellsig.2018.07.013DOI
S0898656818301700Publisher Item Identifier
Divisions: Schools > School of Science and Technology
Depositing User: Jonathan Gallacher
Date Added: 09 Aug 2018 13:09
Last Modified: 31 Jul 2019 03:00
URI: http://irep.ntu.ac.uk/id/eprint/34303

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