Endocrinology, Vol 137, 225-233, Copyright © 1996 by Endocrine Society

ARTICLES

Calcium-mobilizing insulin secretagogues stimulate transcription that is directed by the cyclic adenosine 3',5'-monophosphate/calcium response element in a pancreatic islet beta-cell line

B Eckert, M Schwaninger and W Knepel
Department of Biochemical Pharmacology, University of Gottingen, Germany.

In pancreatic beta-cells, calcium is required for insulin secretion, but can also stimulate gene transcription. High potassium-induced membrane depolarization and calcium influx have previously been shown to activate kinases that phosphorylate and thereby activate the transcription factor cAMP response element (CRE-binding protein (CREB) binding to CREs. It is unknown, however, whether hormones and neurotransmitters can activate this mechanism. Arginine vasopressin (AVP), bombesin, and acetylcholine potentiate glucose-induced insulin secretion and are known to raise cytosolic calcium levels through binding to cell surface receptors that activate phospholipase C. The effect of AVP on CRE-directed transcription was examined in the beta- cell line HIT. AVP (0.1-100 nM) stimulated gene transcription after transient transfection of a reporter gene that was placed under the transcriptional control of a CRE. This effect was inhibited by a vasopressin V1 receptor antagonist and depended on calcium influx and calcineurin phosphatase activity. By immunoblots with antiphospho-CREB antibodies and by using a Gal4-CREB fusion protein, it was shown that AVP induces the phosphorylation and activation of CREB. Like AVP, bombesin (100 nM) and the muscarinic agonist carbachol (200 microM) stimulated CRE-mediated transcription. These results show that calcium- mediating insulin secretagogues can activate CREB/CRE-directed transcription in HIT cells, offering a mechanism by which these secretagogues could produce long term effects on beta-cell function, changing the pattern of gene expression.

This article has been cited by other articles:

				V. Waters, S. Sokol, B. Reddy, G. Soong, J. Chun, and A. Prince The Effect of Cyclosporin A on Airway Cell Proinflammatory Signaling and Pneumonia Am. J. Respir. Cell Mol. Biol., August 1, 2005; 33(2): 138 - 144. [Abstract] [Full Text] [PDF]

				P. Jambal, S. Masterson, A. Nesterova, R. Bouchard, B. Bergman, J. C. Hutton, L. M. Boxer, J. E.-B. Reusch, and S. Pugazhenthi Cytokine-mediated Down-regulation of the Transcription Factor cAMP-response Element-binding Protein in Pancreatic {beta}-Cells J. Biol. Chem., June 13, 2003; 278(25): 23055 - 23065. [Abstract] [Full Text] [PDF]

				M. C. Lawrence, H. S. Bhatt, and R. A. Easom NFAT Regulates Insulin Gene Promoter Activity in Response to Synergistic Pathways Induced by Glucose and Glucagon-Like Peptide-1 Diabetes, March 1, 2002; 51(3): 691 - 698. [Abstract] [Full Text] [PDF]

				M. C. Lawrence, H. S. Bhatt, J. M. Watterson, and R. A. Easom Regulation of Insulin Gene Transcription by a Ca2+-Responsive Pathway Involving Calcineurin and Nuclear Factor of Activated T Cells Mol. Endocrinol., October 1, 2001; 15(10): 1758 - 1767. [Abstract] [Full Text] [PDF]

				G. Siemann, R. Blume, D. Grapentin, E. Oetjen, M. Schwaninger, and W. Knepel Inhibition of Cyclic AMP Response Element-Binding Protein/Cyclic AMP Response Element-Mediated Transcription by the Immunosuppressive Drugs Cyclosporin A and FK506 Depends on the Promoter Context Mol. Pharmacol., June 1, 1999; 55(6): 1094 - 1100. [Abstract] [Full Text]

				P. M. Jones and S. J. Persaud Protein Kinases, Protein Phosphorylation, and the Regulation of Insulin Secretion from Pancreatic {beta}-Cells. Endocr. Rev., August 1, 1998; 19(4): 429 - 461. [Abstract] [Full Text] [PDF]

				A. Haddad and A. P. Turkewitz Analysis of exocytosis mutants indicates close coupling between regulated secretion and transcription activation in Tetrahymena PNAS, September 30, 1997; 94(20): 10675 - 10680. [Abstract] [Full Text] [PDF]

				C. D. Clyne, Y. Zhang, L. Slutsker, J. M. Mathis, P. C. White, and W. E. Rainey Angiotensin II and Potassium Regulate Human CYP11B2 Transcription through Common cis-Elements Mol. Endocrinol., May 1, 1997; 11(5): 638 - 649. [Abstract] [Full Text]