Journal
CELLULAR SIGNALLING
Volume 51, Issue -, Pages 86-98Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2018.07.013
Keywords
Vascular smooth muscle; GRK; Arrestin; Adenosine A(2B )receptor; beta(2)-adrenoceptor
Categories
Funding
- British Heart Foundation of the United Kingdom [RG06/008/22062, PG/11/60/29007, PG/13/95/30603]
- BBSRC [1786881] Funding Source: UKRI
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Generation of CAMP through G,-coupled G protein-coupled receptor (GPCR) [e.g. beta(2) -adrenoceptor (beta(2)AR), adenosine A(2B) receptor (A(2B)R)] activation, induces arterial smooth muscle relaxation, counteracting the actions of vasoconstrictors. G(s)-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 beta(2)AR and A(2B)R 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 beta(2)AR- and A(2B)R-mediated adenylyl cyclase (AC) signalling were determined by assessing cAMP accumulation. GRK2 or GRK5 depletion enhanced and prolonged beta(2)AR/AC signalling, while combined deletion of GRK2/5 has an additive effect. Conversely, activation of AC by A(2B)R was regulated by GRK5, but not GRK2.beta(2)AR 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 A(2B)R-AC signalling and attenuated A(2B)R desensitization, while beta(2)AR-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.
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