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

Bin Xian Zhang, Hong Zhao, Shmuel Muallem

Research output: Contribution to journalArticle

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Abstract

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, Ca 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
Volume268
Issue number15
StatePublished - May 25 1993
Externally publishedYes

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Inositol 1,4,5-Trisphosphate
Phosphoric Monoester Hydrolases
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Phosphotransferases
Phosphoprotein Phosphatases
Chemical activation
Okadaic Acid
Calcium-Calmodulin-Dependent Protein Kinases
Calcineurin
Egtazic Acid
Tacrolimus
Immunosuppressive Agents
Chelating Agents
Cyclosporine
Adenosine Triphosphate

ASJC Scopus subject areas

  • Biochemistry

Cite this

Ca2+-dependent kinase and phosphatase control inositol 1,4,5-trisphosphate-mediated Ca2+ release : Modification by agonist stimulation. / Zhang, Bin Xian; Zhao, Hong; Muallem, Shmuel.

In: Journal of Biological Chemistry, Vol. 268, No. 15, 25.05.1993, p. 10997-11001.

Research output: Contribution to journalArticle

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