DIFFERENTIAL ACTIVATION OF ADENYLYL-CYCLASE BY PROTEIN-KINASE-C ISOENZYMES

Cyclic AMP production within cells is altered upon protein kinase C (P KC) activation; however, whether PKC directly modulates adenylyl cycla se (AC) catalytic activity has been controversial. Molecular studies h ave elucidated the existence of multiple PKC isoenzymes although the f unctional role of this diversity is not clear. Using purified PKC and AC isoenzymes, we demonstrate that PKC zeta directly phosphorylates ty pe VAC, leading to an approximate 20-fold increase in its catalytic ac tivity, a significantly larger enhancement than that achieved with for skolin (similar to 5-fold), the most potent activator of AC. When fors kolin and PKC phosphorylation are combined, type V AC catalytic activi ty is increased 100-fold over basal levels. The two PKC isoenzymes (al pha and zeta) are additive in their capacity to activate AC, although PKC alpha is less potent than PKC zeta. Our data indicate that PKC can directly and potently regulate AC activity in an isoenzyme-specific m anner, suggesting that direct cross-talk plays a major role in coordin ating the activity of these two principal signal transduction pathways .