HORMONE STIMULATION OF TYPE-III ADENYLYL-CYCLASE INDUCES CA2-293 CELLS( OSCILLATIONS IN HEK)

Various forms of cross-talk between the Ca2+ and cAMP signal transduct ion systems can occur in animal cells depending upon the types of aden ylyl cyclases present. Here, we report that Ca2+ oscillations can be g enerated by hormone stimulation of type III adenylyl cyclase expressed in HEK-293 cells. These Ca2+ oscillations are apparently due to the u nique regulatory features of type III adenylyl cyclase, which is stimu lated by hormones and inhibited by elevated Ca2+ in vivo. Ca2+ oscilla tions were generated by glucagon, isoproterenol, or forskolin stimulat ion of type III adenylyl cyclase and were dependent upon the activity of cAMP- and calmodulin-dependent protein kinases. Ca2+ oscillations w ere not solely dependent upon cAMP increases since dibutyryl cAMP or ( S-p)-cAMP did not stimulate Ca2+ oscillations. We hypothesize that sti mulation of type III adenylyl cyclase leads to increased cAMP, activat ion of inositol 1,4,5-trisphosphate receptors, and elevation of intrac ellular Ca2+. As free Ca2+ increases, type III adenylyl cyclase activi ty is attenuated by CaM kinase(s) and intracellular cAMP levels decrea se. When cAMP levels drop below a threshold level, the inositol 1,4,5- trisphosphate receptor is dephosphorylated and Ca2+ is resequestered. This cycle is repeated if type III adenylyl cyclase is chronically exp osed to an activator. This unique mechanism for generation of Ca2+ osc illations in cells is distinct from others documented in the literatur e.