Of nine G protein subunits examined, only and served as substrates for phosphorylation by various isoforms of protein kinase C in vitro. A close homolog of , , was not phosphorylated. Exposure of NIH 3T3 cells that stably express to phorbol 12-myristate 13-acetate also resulted in phosphorylation of the protein. Phosphorylation in vitro occurred near the amino terminus (probably Ser), and approximately 1 mol of phosphate was incorporated per mol of . Although G protein heterotrimers containing either or were poor substrates for phosphorylation, the isolated subunits were phosphorylated equally well in their GDP- or GTPS-bound forms. The guanine nucleotide binding properties of purified and were unaltered by phosphorylation, as was the capacity of to inhibit type V adenylyl cyclase. However, phosphorylation of either protein greatly reduced its affinity for G protein subunits, consistent with the newly determined crystal structure of a G protein heterotrimer. We suggest that protein kinase C regulates - and -mediated signaling pathways by preventing their association with .

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