RGD Reference Report - Differential regulation of ß2-adrenoceptor and adenosine A2B receptor signalling by GRK and arrestin proteins in arterial smooth muscle. - Rat Genome Database

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Differential regulation of ß2-adrenoceptor and adenosine A2B receptor signalling by GRK and arrestin proteins in arterial smooth muscle.

Authors: Nash, Craig A  Nelson, Carl P  Mistry, Rajendra  Moeller-Olsen, Christian  Christofidou, Elena  Challiss, R A John  Willets, Jonathon M 
Citation: Nash CA, etal., Cell Signal. 2018 Nov;51:86-98. doi: 10.1016/j.cellsig.2018.07.013. Epub 2018 Jul 31.
RGD ID: 13792694
Pubmed: PMID:30075183   (View Abstract at PubMed)
DOI: DOI:10.1016/j.cellsig.2018.07.013   (Journal Full-text)

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.



Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  

Objects Annotated

Genes (Rattus norvegicus)
Grk2  (G protein-coupled receptor kinase 2)
Grk5  (G protein-coupled receptor kinase 5)


Additional Information