Phosphorylation and regulation of G-protein βγ-activated phospholipase C-β2 by cAMP-dependent protein kinase

The heterotrimeric G proteins mediate a variety of cellular processes by coupling transmembrane receptors to different effector molecules, including inositol phospholipid-specific phospholipase C (PLC) and adenylyl cyclases. PLC catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate to generate diacylglycerol and inositol 1,4,5-triphosphate, leading to the activation of protein kinase C and the mobilization of intracellular Ca⁺⁺. Activation of adenylyl cyclase results in the production of cAMP and activation of cAMPdependent protein kinase. The various PLC isoforms appears to be activated by different receptors and in some cases by differernt G-protein components. There are four well-characterized forms of PLC-β and all of them are activated by the Goq family proteins. Specific activation of PLC-β isoforms by Gβγ subunits is also observed in some cells and tissues. Although it has been suggested that PLC activation is modulated by the adenylyl cyclase pathway, no clear biochemical links has been established between PLC and cyclic AMP. Here we report that cAMP-dependent protein kinase specifically inhibits the Gβγ-activated PLC-β2 activity, not the Go-activated PLC-β isoforms, and that the effect of PKA is not mimicked by PKC isozymes. Furthermore, we shown that PKA directly phosphorylates serine residues of the PLC-β2 protein both in vivo and in vitro . These results provide a mechanism for the specificity and cross-talk between the two G-protein coupled signal transduction pathways.