Switching of the coupling of the β2-adrenergic receptor to different G proteins by protein kinase A

Yehia Daaka, Louis M. Luttrell and Robert J. Lefkowitz ()
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Yehia Daaka: Howard Hughes Medical Institute
Louis M. Luttrell: Howard Hughes Medical Institute
Robert J. Lefkowitz: Howard Hughes Medical Institute

Nature, 1997, vol. 390, issue 6655, 88-91

Abstract: Abstract Many of the G-protein-coupled receptors for hormones that bind to the cell surface can signal to the interior of the cell through several different classes of G protein1,2,3,4. For example, although most of the actions of the prototype β2-adrenergic receptor are mediated through Gs proteins and the cyclic-AMP-dependent protein kinase (PKA) system5,6, β-adrenergic receptors can also couple to Gi proteins1,2. Here we investigate the mechanism that controls the specificity of this coupling. We show that in HEK293 cells, stimulation of mitogen-activated protein (MAP) kinase by the β2-adrenergic receptor is mediated by the βγ subunits of pertussis-toxin-sensitive G proteins through a pathway involving the non-receptor tyrosine kinase c-Src and the G protein Ras. Activation of this pathway by the β2-adrenergic receptor requires that the receptor be phosphorylated by PKA because it is blocked by H-89, an inhibitor of PKA. Additionally, a mutant of the receptor, which lacks the sites normally phosphorylated by PKA, can activate adenylyl cyclase5, the enzyme that generates cAMP, but not MAP kinase. Our results demonstrate that a mechanism previously shown to mediate uncoupling of the β2-adrenergic receptor from Gs and thus heterologous desensitization7 (PKA-mediated receptor phosphorylation), also serves to ‘switch’ coupling of this receptor from Gs to Gi and initiate a new set of signalling events.

Date: 1997
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DOI: 10.1038/36362

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