PKA-mediated phosphorylation of the beta1-adrenergic receptor promotes Gs/Gi switching

Cell Signal. 2004 Dec;16(12):1397-403. doi: 10.1016/j.cellsig.2004.05.002.


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".

MeSH terms

  • Adenylyl Cyclases / metabolism
  • Animals
  • Binding Sites
  • CHO Cells
  • Cricetinae
  • Cyclic AMP / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Dose-Response Relationship, Drug
  • Enzyme Activation
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism*
  • GTP-Binding Protein alpha Subunits, Gs / metabolism*
  • Mutation
  • Phosphorylation
  • Plasmids / metabolism
  • Receptors, Adrenergic, beta-1 / metabolism*
  • Time Factors
  • Transcriptional Activation
  • Transfection


  • Receptors, Adrenergic, beta-1
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • GTP-Binding Protein alpha Subunits, Gs
  • Adenylyl Cyclases