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. 1980 Sep;66(3):603–607. doi: 10.1172/JCI109893

Possible role for calmodulin in insulin release. Studies with trifluoperazine in rat pancreatic islets.

Y Krausz, C B Wollheim, E Siegel, G W Sharp
PMCID: PMC371690  PMID: 6156956

Abstract

The role of calmodulin in insulin secretion from rat pancreatic islets has been examined by the use of trifluoperazine, an inhibitor of calmodulin-Ca++-directed functions. It was found that 30 microM trifluoperazine caused 50% inhibition, and 100 microM, up to 73% inhibition of 16.7 mM glucose-stimulated insulin release. 100 microM trifluoperazine caused a similar inhibition of 10 mM glyceraldehyde-stimulated release. Therefore, the site of action of trifluoperazine in glucose stimulus-secretion coupling appears to be after the trioses. As trifluoperazine had no effect upon insulin release stimulated by 1 mM 3-isobutyl-1-methylxanthine, the inhibitory effect of trifluoperazine appears to be rather specific. Further, the process of exocytosis per se is not affected. It was also found that although trifluoperazine inhibited the effect of glucose to stimulate insulin release, it did not affect the synergism between glucose and 3-isobutyl-1-methylxanthine to potentiate insulin release. It may be concluded that trifluoperazine selectively inhibits one part of the mechanism by which glucose stimulates insulin release. Calmodulin plays a role in the stimulation of insulin release by glucose at a site between metabolism of trioses and elevation of cytosol Ca++, but is not involved in the final process of exocytosis.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Charles M. A., Fanska R., Schmid F. G., Forsham P. H., Grodsky G. M. Adenosine 3',5'-monophosphate in pancreatic islets: glucose-induced insulin release. Science. 1973 Feb 9;179(4073):569–571. doi: 10.1126/science.179.4073.569. [DOI] [PubMed] [Google Scholar]
  2. Charles M. A., Lawecki J., Pictet R., Grodsky G. M. Insulin secretion. Interrelationships of glucose, cyclic adenosine 3:5-monophosphate, and calcium. J Biol Chem. 1975 Aug 10;250(15):6134–6140. [PubMed] [Google Scholar]
  3. Cheung W. Y. Calmodulin plays a pivotal role in cellular regulation. Science. 1980 Jan 4;207(4426):19–27. doi: 10.1126/science.6243188. [DOI] [PubMed] [Google Scholar]
  4. Grill V., Cerasi E. Activation by glucose of adenyl cyclase in pancreatic islets of the rat. FEBS Lett. 1973 Jul 15;33(3):311–314. doi: 10.1016/0014-5793(73)80218-2. [DOI] [PubMed] [Google Scholar]
  5. Herbert V., Lau K. S., Gottlieb C. W., Bleicher S. J. Coated charcoal immunoassay of insulin. J Clin Endocrinol Metab. 1965 Oct;25(10):1375–1384. doi: 10.1210/jcem-25-10-1375. [DOI] [PubMed] [Google Scholar]
  6. Karl R. C., Zawalich W. S., Ferrendelli J. A., Matschinsky F. M. The role of Ca-2+ and cyclic adenosine 3':5'-monophosphate in insulin release induced in vitro by the divalent cation ionophore A23187. J Biol Chem. 1975 Jun 25;250(12):4575–4579. [PubMed] [Google Scholar]
  7. Lacy P. E., Kostianovsky M. Method for the isolation of intact islets of Langerhans from the rat pancreas. Diabetes. 1967 Jan;16(1):35–39. doi: 10.2337/diab.16.1.35. [DOI] [PubMed] [Google Scholar]
  8. Levin R. M., Weiss B. Binding of trifluoperazine to the calcium-dependent activator of cyclic nucleotide phosphodiesterase. Mol Pharmacol. 1977 Jul;13(4):690–697. [PubMed] [Google Scholar]
  9. Levin R. M., Weiss B. Mechanism by which psychotropic drugs inhibit adenosine cyclic 3',5'-monophosphate phosphodiesterase of brain. Mol Pharmacol. 1976 Jul;12(4):581–589. [PubMed] [Google Scholar]
  10. Malaisse W. J., Herchuelz A., Levy J., Sener A., Pipeleers D. G., Devis G., Somers G., Obberghen E. V. The stimulus-secretion coupling of glucose-induced insulin release XIX. The insulinotropic effect of glyceraldehyde. Mol Cell Endocrinol. 1975 Dec;4(1):1–12. doi: 10.1016/0303-7207(76)90002-2. [DOI] [PubMed] [Google Scholar]
  11. Sharp G. W. The adenylate cyclase-cyclic AMP system in islets of Langerhans and its role in the control of insulin release. Diabetologia. 1979 May;16(5):287–296. doi: 10.1007/BF01223617. [DOI] [PubMed] [Google Scholar]
  12. Sharp G. W., Wiedenkeller D. E., Kaelin D., Siegel E. G., Wollheim C. B. Stimulation of adenylate cyclase by Ca2+ and calmodulin in rat islets of langerhans: explanation for the glucose-induced increase in cyclic AMP levels. Diabetes. 1980 Jan;29(1):74–77. doi: 10.2337/diab.29.1.74. [DOI] [PubMed] [Google Scholar]
  13. Siegel E. G., Wollheim C. B., Kikuchi M., Renold A. E., Sharp G. W. Dependency of cyclic AMP-induced insulin release on intra- and extracellular calcium in rat islets of Langerhans. J Clin Invest. 1980 Feb;65(2):233–241. doi: 10.1172/JCI109665. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Sugden M. C., Christie M. R., Ashcroft S. J. Presence and possible role of calcium-dependent regulator (calmodulin) in rat islets of Langerhans. FEBS Lett. 1979 Sep 1;105(1):95–100. doi: 10.1016/0014-5793(79)80894-7. [DOI] [PubMed] [Google Scholar]
  15. Valverde I., Vandermeers A., Anjaneyulu R., Malaisse W. J. Calmodulin activation of adenylate cyclase in pancreatic islets. Science. 1979 Oct 12;206(4415):225–227. doi: 10.1126/science.225798. [DOI] [PubMed] [Google Scholar]
  16. Weiss B., Levin R. M. Mechanism for selectively inhibiting the activation of cyclic nucleotide phosphodiesterase and adenylate cyclase by antipsychotic agents. Adv Cyclic Nucleotide Res. 1978;9:285–303. [PubMed] [Google Scholar]
  17. Wolff D. J., Brostrom C. O. Properties and functions of the calcium-dependent regulator protein. Adv Cyclic Nucleotide Res. 1979;11:27–88. [PubMed] [Google Scholar]
  18. Wollheim C. B., Blondel B., Trueheart P. A., Renold A. E., Sharp G. W. Calcium-induced insulin release in monolayer culture of the endocrine pancreas. Studies with ionophore A23187. J Biol Chem. 1975 Feb 25;250(4):1354–1360. [PubMed] [Google Scholar]
  19. Wollheim C. B., Kikuchi M., Renold A. E., Sharp G. W. The roles of intracellular and extracellular Ca++ in glucose-stimulated biphasic insulin release by rat islets. J Clin Invest. 1978 Aug;62(2):451–458. doi: 10.1172/JCI109146. [DOI] [PMC free article] [PubMed] [Google Scholar]

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