PKA-mediated phosphorylation of the beta1-adrenergic receptor promotes Gs/Gi switching.
Journal Article
Recently, it has been shown that PKA-mediated phosphorylation of the beta(2)-adrenergic receptor (beta(2)-AR) by the cyclic AMP-dependent protein kinase (PKA) reduces its affinity for G(s) and increases its affinity for G(i). Here we demonstrate that, like the beta(2)-AR, the beta(1)-AR is also capable of "switching" its coupling from G(s) to G(i) in a PKA-dependent manner. The beta(1)-AR is capable of activating adenylate cyclase via G(s), and can also activate the extracellular-regulated kinases, p44 and p42 (ERK1/2). In transfected CHO cells, the observed beta(1)-AR-mediated activation of ERK is both sensitive to pertussis toxin (PTX), indicating involvement of G(i)/G(o), and to the PKA inhibitor, H-89. beta(1)-ARs with PKA phosphorylation sites mutated to alanines are unable to activate ERK. Mutating these same residues to aspartic acid, mimicking PKA phosphorylation, leads to a decrease in G(s)-stimulated cAMP accumulation and an increase in PTX-sensitive ERK activation. These results strongly support the hypothesis that the beta(1)-AR, like the beta(2)-AR, can undergo PKA-dependent "G(s)/G(i) switching".
Full Text
Duke Authors
Cited Authors
- Martin, NP; Whalen, EJ; Zamah, MA; Pierce, KL; Lefkowitz, RJ
Published Date
- December 2004
Published In
Volume / Issue
- 16 / 12
Start / End Page
- 1397 - 1403
PubMed ID
- 15381255
Pubmed Central ID
- 15381255
International Standard Serial Number (ISSN)
- 0898-6568
Digital Object Identifier (DOI)
- 10.1016/j.cellsig.2004.05.002
Language
- eng
Conference Location
- England