Diabetes, Vol 45, Issue 3 295-301, Copyright © 1996 by American Diabetes Association

ARTICLES

cAMP-signaling pathway acts in selective synergism with glucose or tolbutamide to increase cytosolic Ca2+ in rat pancreatic beta-cells

K Yaekura, M Kakei and T Yada
Department of Physiology, Kagoshima University School of Medicine, Japan.

cAMP and the insulinotropic peptides that raise cAMP glucose-dependently increase the cytosolic free Ca2+ concentration ([Ca2+]i) in pancreatic beta-cells, which is tightly linked to the potentiation of glucose-induced insulin release. We examined whether cAMP increases [Ca2+]i in specific cooperation only with glucose or also with other insulin secretagogues that act through different mechanisms. [Ca2+]i in single rat pancreatic beta-cells was measured by dual-wavelength fura-2 microfluorometry. In the presence of a stimulatory concentration of glucose (8.3 mmol/l) and the moderate elevation in [Ca2+]i induced by it, forskolin, an activator of adenylyl cyclase, or dibutyryl cAMP produced a marked additional increase in [Ca2+]i but was ineffective at the basal 2.8 mmol/l glucose. These cAMP-elevating agents also potentiated the effect of tolbutamide on [Ca2+]i. The cAMP-induced increase in [Ca2+]i was completely and selectively inhibited by a blocker of cAMP-dependent protein kinase A (PKA), and by nitrendipine, a blocker of the L-type Ca2+ channel. However, in the presence of high KCl and the [Ca2+]i elevation induced by it, a rise in cAMP failed to further increase [Ca2+]i, whereas BAY K8644, an agonist of L-type Ca2+ channels, evoked an additional increase in [Ca2+]i. Under low Na+ conditions, the [Ca2+]i response to cAMP was observed in the majority of the cells. In the cells in which glucose at 4.5-5 mmol/l was inadequate to increase [Ca2+]i, the glucose together with a rise in cAMP often increased [Ca2+]i. Likewise, tolbutamide and a rise in cAMP acted in concert to increase [Ca2+]i. Thus, cAMP left-shifted the concentration-[Ca2+]i response relationship for glucose and tolbutamide. In conclusion, the cAMP-PKA pathway acts in selective synergism with glucose and tolbutamide to initiate [Ca2+]i signals in pancreatic beta- cells. cAMP appears to regulate beta-cell sensitivity to glucose and tolbutamide. In contrast, cAMP fails to cooperate with high KCl to increase [Ca2+]i. It is suggested that cAMP acts mainly on a site that is more proximal but functionally linked to the L-type Ca2+ channel, thereby finally increasing Ca2+ influx through this channel.
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				J. Zhang, Z. Xie, Y. Dong, S. Wang, C. Liu, and M.-H. Zou Identification of Nitric Oxide as an Endogenous Activator of the AMP-activated Protein Kinase in Vascular Endothelial Cells J. Biol. Chem., October 10, 2008; 283(41): 27452 - 27461. [Abstract] [Full Text] [PDF]

				J. de Heer and J. J. Holst Sulfonylurea Compounds Uncouple the Glucose Dependence of the Insulinotropic Effect of Glucagon-Like Peptide 1 Diabetes, February 1, 2007; 56(2): 438 - 443. [Abstract] [Full Text] [PDF]

				T S McQuaid, M C Saleh, J W Joseph, A Gyulkhandanyan, J E Manning-Fox, J D MacLellan, M B Wheeler, and C B Chan cAMP-mediated signaling normalizes glucose-stimulated insulin secretion in uncoupling protein-2 overexpressing {beta}-cells. J. Endocrinol., September 1, 2006; 190(3): 669 - 680. [Abstract] [Full Text] [PDF]

				H. Hatakeyama, T. Kishimoto, T. Nemoto, H. Kasai, and N. Takahashi Rapid glucose sensing by protein kinase A for insulin exocytosis in mouse pancreatic islets J. Physiol., January 15, 2006; 570(2): 271 - 282. [Abstract] [Full Text] [PDF]

				C. S. Nunemaker, M. Zhang, and L. S. Satin Insulin Feedback Alters Mitochondrial Activity Through an ATP-sensitive K+ Channel-Dependent Pathway in Mouse Islets and {beta}-Cells Diabetes, July 1, 2004; 53(7): 1765 - 1772. [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]

				H. Kasai, T. Suzuki, T.-T. Liu, T. Kishimoto, and N. Takahashi Fast and cAMP-Sensitive Mode of Ca2+-Dependent Exocytosis in Pancreatic {beta}-Cells Diabetes, February 1, 2002; 51(90001): S19 - 24. [Abstract] [Full Text] [PDF]

				C. Fernandez-Mejia, J. Vega-Allende, A. Rojas-Ochoa, M. Rodriguez-Dorantes, G. Romero-Navarro, F. M. Matschinsky, J. Wang, and M. S. German Cyclic Adenosine 3',5'-Monophosphate Increases Pancreatic Glucokinase Activity and Gene Expression Endocrinology, April 1, 2001; 142(4): 1448 - 1452. [Abstract] [Full Text]

				S. Hashiguchi, T. Yada, and T. Arima A New Hypoglycemic Agent, JTT-608, Evokes Protein Kinase A-Mediated Ca2+ Signaling in Rat Islet {beta}-Cells: Strict Regulation by Glucose, Link to Insulin Release, and Cooperation with Glucagon-Like Peptide-1(7-36)amide and Pituitary Adenylate Cyclase-Activating Polypeptide J. Pharmacol. Exp. Ther., January 1, 2001; 296(1): 22 - 30. [Abstract] [Full Text]

				M. Kajikawa, H. Ishida, S. Fujimoto, E. Mukai, M. Nishimura, J. Fujita, Y. Tsuura, Y. Okamoto, A. W. Norman, and Y. Seino An Insulinotropic Effect of Vitamin D Analog with Increasing Intracellular Ca2+ Concentration in Pancreatic {beta}-Cells through Nongenomic Signal Transduction Endocrinology, October 1, 1999; 140(10): 4706 - 4712. [Abstract] [Full Text]

				H.-P. Bode, B. Moormann, R. Dabew, and B. Göke Glucagon-Like Peptide 1 Elevates Cytosolic Calcium in Pancreatic {beta}-Cells Independently of Protein Kinase A Endocrinology, September 1, 1999; 140(9): 3919 - 3927. [Abstract] [Full Text]

				N. Takahashi, T. Kadowaki, Y. Yazaki, G. C. R. Ellis-Davies, Y. Miyashita, and H. Kasai Post-priming actions of ATP on Ca2+-dependent exocytosis in pancreatic beta cells PNAS, January 19, 1999; 96(2): 760 - 765. [Abstract] [Full Text] [PDF]

				K. Yaekura and T. Yada [Ca2+]i-reducing action of cAMP in rat pancreatic beta -cells: involvement of thapsigargin-sensitive stores Am J Physiol Cell Physiol, February 1, 1998; 274(2): C513 - C521. [Abstract] [Full Text] [PDF]

				L. B. Lester, L. K. Langeberg, and J. D. Scott Anchoring of protein kinase A facilitates hormone-mediated insulin secretion PNAS, December 23, 1997; 94(26): 14942 - 14947. [Abstract] [Full Text] [PDF]

				Z. Ma, S. Ramanadham, M. Wohltmann, A. Bohrer, F.-F. Hsu, and J. Turk Studies of Insulin Secretory Responses and of Arachidonic Acid Incorporation into Phospholipids of Stably Transfected Insulinoma Cells That Overexpress Group VIA Phospholipase A2 (iPLA2beta ) Indicate a Signaling Rather Than a Housekeeping Role for iPLA2beta J. Biol. Chem., April 13, 2001; 276(16): 13198 - 13208. [Abstract] [Full Text] [PDF]

				C. Wasmeier and J. C. Hutton Secretagogue-dependent Phosphorylation of the Insulin Granule Membrane Protein Phogrin Is Mediated by cAMP-dependent Protein Kinase J. Biol. Chem., August 17, 2001; 276(34): 31919 - 31928. [Abstract] [Full Text] [PDF]

				Z. Ma, S. Zhang, J. Turk, and S. Ramanadham Stimulation of insulin secretion and associated nuclear accumulation of iPLA2beta in INS-1 insulinoma cells Am J Physiol Endocrinol Metab, April 1, 2002; 282(4): E820 - E833. [Abstract] [Full Text] [PDF]

				M. Nakazaki, M. Kakei, H. Ishihara, N. Koriyama, H. Hashiguchi, K. Aso, M. Fukudome, Y. Oka, T. Yada, and C. Tei Association of upregulated activity of KATP channels with impaired insulin secretion in UCP1-expressing insulinoma cells J. Physiol., May 1, 2002; 540(3): 781 - 789. [Abstract] [Full Text] [PDF]