Hormone stimulation of type III adenylyl cyclase induces Ca2+ oscillations in HEK-293 cells.
Various forms of cross-talk between the Ca2+ and cAMP signal transduction systems can occur in animal cells depending upon the types of adenylyl cyclases present. Here, we report that Ca2+ oscillations can be generated by hormone stimulation of type III adenylyl cyclase expressed in HEK-293 cells. These Ca2+ oscillations are apparently due to the unique regulatory features of type III adenylyl cyclase, which is stimulated by hormones and inhibited by elevated Ca2+ in vivo. Ca2+ oscillations were generated by glucagon, isoproterenol, or forskolin stimulation of type III adenylyl cyclase and were dependent upon the activity of cAMP- and calmodulin-dependent protein kinases. Ca2+ oscillations were not solely dependent upon cAMP increases since dibutyryl cAMP or (Sp)-cAMP did not stimulate Ca2+ oscillations. We hypothesize that stimulation of type III adenylyl cyclase leads to increased cAMP, activation of inositol 1,4,5-trisphosphate receptors, and elevation of intracellular Ca2+. As free Ca2+ increases, type III adenylyl cyclase activity is attenuated by CaM kinase(s) and intracellular cAMP levels decrease. 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 exposed to an activator. This unique mechanism for generation of Ca2+ oscillations in cells is distinct from others documented in the literature.
Wayman
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Department of Pharmacology, University of Washington, Seattle 98195, USA.
Hinds
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D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives*; D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002217:Carbachol / Q000494:pharmacology; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005934:Glucagon / Q000494:pharmacology*; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007545:Isoproterenol / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology; D007668:Kidney; D007700:Kinetics; D008954:Models, Biological; D009991:Oscillometry; D010716:Phosphatidylinositols / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D018027:Receptors, Glucagon / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction; D013997:Time Factors
D015220:Calcium Channels; D004791:Enzyme Inhibitors; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007546:Isoquinolines; D010716:Phosphatidylinositols; D010879:Piperazines; D018160:Receptors, Cytoplasmic and Nuclear; D018027:Receptors, Glucagon; D005576:Colforsin; C063302:KN 62; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D002217:Carbachol; D005934:Glucagon; D000242:Cyclic AMP; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine