Ca2+-induced loss of Ca2+/calmodulin-dependent protein  kinase II activity in pancreatic β-cells

Elevations in intracellular Ca2+ in electrically permeabilized islets of Langerhans produced rapid insulin secretory responses from β-cells, but the Ca2+-induced secretion was not maintained and was irrespective of the pattern of administration of elevated Ca2+. Ca2+-insensitive β-cells responded normally to activators of protein kinase C or cAMP-dependent kinase with increased insulin secretion. The loss of secretory responsiveness to Ca2+ was paralleled by a reduction in Ca2+-induced protein phosphorylation. This was caused by a reduction in Ca2+/calmodulin-dependent protein kinase II (CaMK II) activity in the desensitized cells, as assessed by measuring the phosphorylation of a CaMK II-specific exogenous substrate, autocamtide-2. The Ca2+-induced reductions in kinase activity and protein phosphorylation were not dependent on the activation of Ca2+-dependent protein kinases and were not caused by the activation of phosphoprotein phosphatases or of Ca2+-activated proteases. The concomitant reductions in CaMK II activity and Ca2+-induced insulin secretion suggest that the activation of CaMK II is required for normal insulin secretory responses to increased intracellular Ca2+ concentrations.

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Dependence of insulin secretion from permeabilized pancreatic β-cells on the activation of Ca2+/calmodulin-dependent protein kinase II

Biochemical Pharmacology ◽

10.1016/s0006-2952(00)00483-4 ◽

2000 ◽

Vol 60 (11) ◽

pp. 1655-1663 ◽

Cited By ~ 29

Author(s):

Harshika S Bhatt ◽

Barry P Conner ◽

Ganesh Prasanna ◽

Thomas Yorio ◽

Richard A Easom

Keyword(s):

Insulin Secretion ◽

Protein Kinase ◽

Β Cells ◽

Pancreatic Β Cells ◽

Dependent Protein Kinase ◽

Protein Kinase Ii ◽

Dependent Protein

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2,5-hexanedione (HD) treatment alters calmodulin, Ca2+/calmodulin-dependent protein kinase II, and protein kinase C in rats' nerve tissues

Toxicology and Applied Pharmacology ◽

10.1016/j.taap.2008.05.021 ◽

2008 ◽

Vol 232 (1) ◽

pp. 60-68 ◽

Cited By ~ 5

Author(s):

Qing-Shan Wang ◽

Li-Yan Hou ◽

Cui-Li Zhang ◽

Xiu-Lan Zhao ◽

Su-Fang Yu ◽

...

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Dependent Protein Kinase ◽

Kinase C ◽

Protein Kinase Ii ◽

Dependent Protein

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Ca2+-induced insulin secretion from electrically permeabilized islets. Loss of the Ca2+-induced secretory response is accompanied by loss of Ca2+-induced protein phosphorylation

Biochemical Journal ◽

10.1042/bj2850973 ◽

1992 ◽

Vol 285 (3) ◽

pp. 973-978 ◽

Cited By ~ 24

Author(s):

P M Jones ◽

S J Persaud ◽

S L Howell

Keyword(s):

Protein Kinase C ◽

Insulin Secretion ◽

Protein Kinase ◽

Cyclic Amp ◽

Protein Phosphorylation ◽

Prolonged Exposure ◽

Kinase C ◽

Dependent Protein ◽

32P Incorporation ◽

Rat Islets Of Langerhans

Increasing the cytosolic Ca2+ concentration of electrically permeabilized rat islets of Langerhans caused rapid increases in insulin secretion and in 32P incorporation into islet proteins. However, the secretory responsiveness of permeabilized islets was relatively transient, with insulin secretion approaching basal levels within 20-30 min despite the continued presence of stimulatory concentrations of Ca2+. The loss of Ca2(+)-induced insulin secretion was accompanied by a marked reduction in Ca2(+)-dependent protein phosphorylation, but not in cyclic AMP-dependent protein phosphorylation. Similarly, permeabilized islets which were no longer responsive to Ca2+ were able to mount appropriate secretory responses to cyclic AMP and to a protein kinase C-activating phorbol ester. These results suggest that prolonged exposure to elevated cytosolic Ca2+ concentrations results in a specific desensitization of the secretory mechanism to Ca2+, perhaps as a result of a decrease in Ca2(+)-dependent kinase activity. Furthermore, these studies suggest that secretory responses of B-cells to cyclic AMP and activators of protein kinase C are not dependent upon the responsiveness of the cells to changes in cytosolic Ca2+.

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Muscarinic activation of Ca2+/calmodulin-dependent protein kinase II in pancreatic islets. Temporal dissociation of kinase activation and insulin secretion

Biochemical Journal ◽

10.1042/bj3170167 ◽

1996 ◽

Vol 317 (1) ◽

pp. 167-172 ◽

Cited By ~ 12

Author(s):

Eric L. BABB ◽

Jim TARPLEY ◽

Michael LANDT ◽

Richard A. EASOM

Keyword(s):

Insulin Secretion ◽

Protein Kinase ◽

Pancreatic Islets ◽

Cam Kinase Ii ◽

Muscarinic Agonist ◽

Cam Kinase ◽

Dependent Protein Kinase ◽

Kinase Activation ◽

Protein Kinase Ii ◽

Dependent Protein

We have demonstrated previously that glucose activates the multifunctional Ca2+/calmodulin-dependent protein kinase II (CaM kinase II) in isolated rat pancreatic islets in a manner consistent with a role of this enzyme in the regulation of insulin secretion [Wenham, Landt and Easom (1994) J. Biol. Chem. 269, 4947–4952]. In the current study, the muscarinic agonist, carbachol, has been shown to induce the conversion of CaM kinase II into a Ca2+-independent, autonomous form indicative of its activation. Maximal activation (2-fold) was achieved by 15 s, followed by a rapid return to basal levels by 1 min. This response was primarily the result of the mobilization of Ca2+ from intracellular stores since it was not affected by a concentration (20 μM) of verapamil that completely prevented the activation of CaM kinase II by glucose. Surprisingly, carbachol added prior to, or simultaneously with, glucose attenuated nutrient activation of CaM kinase II. This effect was mimicked by cholecystokinin-8 (CCK-8) and thapsigargin, suggesting its mediation by phospholipase C and the mobilization of intracellular Ca2+. In contrast, carbachol, CCK-8 and thapsigargin markedly potentiated glucose (12 mM)-induced insulin secretion. These results suggest that CaM kinase II activation can be temporally dissociated from insulin secretion but do not exclude the potential dependence of insulin exocytosis on CaM kinase II-mediated protein phosphorylation.

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