Elevation of cytosolic free Ca inhibits the type VI adenylyl cyclase that predominates in C6-2B cells. However, it is not known whether there is any selective requirement for Ca entry or release for inhibition of cAMP accumulation to occur. In the present study, the effectiveness of intracellular Ca release evoked by three independent methods (thapsigargin, ionomycin, and UTP) was compared with the capacitative Ca entry that was triggered by these treatments. In each situation, only Ca entry could inhibit cAMP accumulation (La ions blocked the effect); Ca release, which was substantial in some cases, was without effect. A moderate inhibition, as was elicited by a modest degree of Ca entry, could be rendered substantial in the absence of phosphodiesterase inhibitors. Such conditions more closely mimic the physiological situation of normal cells. These results are particularly significant, in demonstrating not only that Ca entry mediates the inhibitory effects of Ca on cAMP accumulation, but also that diffuse elevations in [Ca] are ineffective in modulating cAMP synthesis. This property suggests that, as with certain Ca-sensitive ion channels, Ca-sensitive adenylyl cyclases may be functionally colocalized with Ca entry channels.

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