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Cell Signal ; 51: 86-98, 2018 11.
Article in English | MEDLINE | ID: mdl-30075183

ABSTRACT

Generation of cAMP through Gs-coupled G protein-coupled receptor (GPCR) [e.g. ß2-adrenoceptor (ß2AR), 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 ß2AR 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 ß2AR- and A2BR-mediated adenylyl cyclase (AC) signalling were determined by assessing cAMP accumulation. GRK2 or GRK5 depletion enhanced and prolonged ß2AR/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. ß2AR 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 ß2AR-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.


Subject(s)
Aorta/metabolism , G-Protein-Coupled Receptor Kinase 2/physiology , G-Protein-Coupled Receptor Kinase 5/physiology , G-Protein-Coupled Receptor Kinases/physiology , Muscle, Smooth/metabolism , Myocytes, Smooth Muscle/metabolism , Receptor, Adenosine A2B/metabolism , Receptors, Adrenergic, beta-2/metabolism , beta-Arrestin 2/physiology , Adenylyl Cyclases/metabolism , Animals , Aorta/cytology , Arrestins/genetics , Arrestins/physiology , Cells, Cultured , G-Protein-Coupled Receptor Kinase 2/genetics , G-Protein-Coupled Receptor Kinase 5/genetics , Muscle, Smooth/cytology , Myocytes, Smooth Muscle/cytology , Rats , Rats, Wistar , Signal Transduction , beta-Arrestin 2/genetics
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