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

被引:40
作者
WAYMAN, GA [1 ]
HINDS, TR [1 ]
STORM, DR [1 ]
机构
[1] UNIV WASHINGTON,DEPT PHARMACOL,SEATTLE,WA 98195
关键词
D O I
10.1074/jbc.270.41.24108
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 (S-p)-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.
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页码:24108 / 24115
页数:8
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