Ca2+-dependent kinase and phosphatase control inositol 1,4,5- trisphosphate-mediated Ca2+ release. Modification by agonist stimulation

B. X. Zhang, H. Zhao, S. Muallem

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82 Scopus citations


A permeable cell system in which Ca2+ release can be evoked by inositol 1,4,5-trisphosphate (IP3) or agonist stimulation was used to study the regulation of Ca2+ release by Ca2+ itself. At low concentrations, Ca2+ activated IP3-mediated Ca2+ release (IMCR) with half-maximal effect at about 15 nM. At high concentrations, Ca2+ inhibited IMCR giving rise to a biphasic [Ca2+] dependence of IMCR. The activation of IMCR by Ca2+ appears to be mediated by a kinase, probably the Ca2+- and calmodulin- dependent protein kinase (CaMKII). Thus, the activation required MgATP, completely blocked at 0 °C, required Ca2+, and was inhibited by the CaMKII inhibitors KT5926 and KN62. The inhibition of IMCR seems to be mediated by a protein phosphatase, probably the Ca2+-dependent protein phosphatase 2B. Hence, the inhibition required Ca2+, was prevented by the general protein phosphatase inhibitor pyrophosphate and by the immunosuppressants cyclosporin A and FK506, but not by okadaic acid or VO4/2-, and was modified by chelating agents such as EGTA. Stimulation with agonists modified the activities of the kinase and phosphatase to make the release independent of [Ca2+]. This appears to be due to an increase in the apparent affinity for Ca2+ in stimulating IMCR and inhibition of the phosphatase. We suggest that agonist-dependent modification of the kinase/phosphatase activity ratio can be the biochemical pathway responsible for regulation of Ca2+ release and in turn [Ca2+](i) oscillations.

Original languageEnglish (US)
Pages (from-to)10997-11001
Number of pages5
JournalJournal of Biological Chemistry
Issue number15
StatePublished - 1993

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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