Diabetes, Vol 49, Issue 3 311-318, Copyright © 2000 by American Diabetes Association

ARTICLES

Diverse roles of K(ATP) channels learned from Kir6.2 genetically engineered mice

S Seino, T Iwanaga, K Nagashima and T Miki
Department of Molecular Medicine, Chiba University Graduate School of Medicine, Japan. seino@molmed.m.chiba-u.ac.jp

The regulation of insulin secretion from pancreatic beta-cells depends critically on the activities of their plasma membrane ion channels. ATP-sensitive K+ channels (K(ATP) channels) are present in many cells and regulate a variety of cellular functions by coupling cell metabolism with membrane potential. The activity of the K(ATP) channels in pancreatic beta-cells is regulated by changes in the ATP and ADP concentrations (ATP/ADP ratio) caused by glucose metabolism. Thus, the K(ATP) channels are the ATP and ADP sensors in the regulation of glucose-induced insulin secretion. K(ATP) channels are also the target of sulfonylureas, which are widely used in the treatment of type 2 diabetes. Molecular cloning of the two subunits of the pancreatic beta-cell K(ATP) channel, Kir6.2 (an inward rectifier K+ channel member) and SUR1 (a receptor for sulfonylureas), has provided great insight into its structure and function. Kir6.2 subunits form the K+ ion-permeable pore and primarily confer inhibition of the channels by ATP, while SUR1 subunits confer activation of the channels by MgADP and K+ channel openers, such as diazoxide, as well as inhibition by sulfonylureas. The SUR1 subunits also enhance the sensitivity of the channels to ATP. To determine the physiological roles of K(ATP) channels directly, we have generated two kinds of genetically engineered mice: mice expressing a dominant-negative form of Kir6.2 specifically in the pancreatic beta-cells (Kir6.2G132S Tg mice) and mice lacking Kir6.2 (Kir6.2 knockout mice). Studies of these mice elucidated various roles of the K(ATP) channels in endocrine pancreatic function: 1) the K(ATP) channels are the major determinant of the resting membrane potential of pancreatic beta-cells, 2) both glucose- and sulfonylurea-induced membrane depolarization of beta-cells require closure of the K(ATP) channels, 3) both glucose- and sulfonylurea-induced rises in intracellular calcium concentration in beta-cells require closure of the K(ATP) channels, 4) both glucose- and sulfonylurea-induced insulin secretions are mediated principally by the K(ATP) channel-dependent pathway, 5) the K(ATP) channels are important for beta-cell survival and architecture of the islets, 6) the K(ATP) channels are important in the differentiation of islet cells, and 7) the K(ATP) channels in glucose-responsive cells generally participate in coupling glucose sensing with cell excitability. Interestingly, despite the severe defect in glucose-induced insulin secretion, Kir6.2 knockout mice show only a very mild impairment in glucose tolerance. However, when the knockout mice become obese with age, they develop fasting hyperglycemia and glucose intolerance, while neither fasting hyperglycemia nor glucose intolerance is evident in the aged knockout mice without obesity, suggesting that both the genetic defect in glucose-induced insulin secretion and the acquired insulin resistance due to environmental factors are necessary to develop diabetes in Kir6.2 knockout mice. Thus, Kir6.2G132S Tg mice and Kir6.2 knockout mice provide a model of type 2 diabetes and clarify the various roles of K(ATP) channels in endocrine pancreatic function.
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				Y. M. Leung, E. P. Kwan, B. Ng, Y. Kang, and H. Y. Gaisano SNAREing Voltage-Gated K+ and ATP-Sensitive K+ Channels: Tuning {beta}-Cell Excitability with Syntaxin-1A and Other Exocytotic Proteins Endocr. Rev., October 1, 2007; 28(6): 653 - 663. [Abstract] [Full Text] [PDF]

				A. Szollosi, M. Nenquin, and J.-C. Henquin Overnight Culture Unmasks Glucose-induced Insulin Secretion in Mouse Islets Lacking ATP-sensitive K+ Channels by Improving the Triggering Ca2+ Signal J. Biol. Chem., May 18, 2007; 282(20): 14768 - 14776. [Abstract] [Full Text] [PDF]

				W. Ma, J. Berg, and G. Yellen Ketogenic Diet Metabolites Reduce Firing in Central Neurons by Opening KATP Channels J. Neurosci., April 4, 2007; 27(14): 3618 - 3625. [Abstract] [Full Text] [PDF]

				P. Moulin, Y. Guiot, J.-C. Jonas, J. Rahier, O. Devuyst, and J.-C. Henquin Identification and subcellular localization of the Na+/H+ exchanger and a novel related protein in the endocrine pancreas and adrenal medulla J. Mol. Endocrinol., March 1, 2007; 38(3): 409 - 422. [Abstract] [Full Text] [PDF]

				A. Szollosi, M. Nenquin, L. Aguilar-Bryan, J. Bryan, and J.-C. Henquin Glucose Stimulates Ca2+ Influx and Insulin Secretion in 2-Week-old beta-Cells Lacking ATP-sensitive K+ Channels J. Biol. Chem., January 19, 2007; 282(3): 1747 - 1756. [Abstract] [Full Text] [PDF]

				P. Stiernet, Y. Guiot, P. Gilon, and J.-C. Henquin Glucose Acutely Decreases pH of Secretory Granules in Mouse Pancreatic Islets: MECHANISMS AND INFLUENCE ON INSULIN SECRETION J. Biol. Chem., August 4, 2006; 281(31): 22142 - 22151. [Abstract] [Full Text] [PDF]

				S. Bao, H. Song, M. Wohltmann, S. Ramanadham, W. Jin, A. Bohrer, and J. Turk Insulin Secretory Responses and Phospholipid Composition of Pancreatic Islets from Mice That Do Not Express Group VIA Phospholipase A2 and Effects of Metabolic Stress on Glucose Homeostasis J. Biol. Chem., July 28, 2006; 281(30): 20958 - 20973. [Abstract] [Full Text] [PDF]

				N. Ishiyama, M. A. Ravier, and J.-C. Henquin Dual mechanism of the potentiation by glucose of insulin secretion induced by arginine and tolbutamide in mouse islets Am J Physiol Endocrinol Metab, March 1, 2006; 290(3): E540 - E549. [Abstract] [Full Text] [PDF]

				Z. Ling, Q. Wang, G. Stange, P. In't Veld, and D. Pipeleers Glibenclamide Treatment Recruits {beta}-Cell Subpopulation Into Elevated and Sustained Basal Insulin Synthetic Activity Diabetes, January 1, 2006; 55(1): 78 - 85. [Abstract] [Full Text] [PDF]

				J. C. Koster, M. A. Permutt, and C. G. Nichols Diabetes and Insulin Secretion: The ATP-Sensitive K+ Channel (KATP) Connection Diabetes, November 1, 2005; 54(11): 3065 - 3072. [Abstract] [Full Text] [PDF]

				A. L. Gloyn, F. Reimann, C. Girard, E. L. Edghill, P. Proks, E. R. Pearson, I. K. Temple, D. J.G. Mackay, J. P.H. Shield, D. Freedenberg, et al. Relapsing diabetes can result from moderately activating mutations in KCNJ11 Hum. Mol. Genet., April 1, 2005; 14(7): 925 - 934. [Abstract] [Full Text] [PDF]

				V. Bancila, T. Cens, D. Monnier, F. Chanson, C. Faure, Y. Dunant, and A. Bloc Two SUR1-specific Histidine Residues Mandatory for Zinc-induced Activation of the Rat KATP Channel J. Biol. Chem., March 11, 2005; 280(10): 8793 - 8799. [Abstract] [Full Text] [PDF]

				J.-C. Henquin Pathways in Beta-Cell Stimulus-Secretion Coupling as Targets for Therapeutic Insulin Secretagogues Diabetes, December 1, 2004; 53(suppl_3): S48 - S58. [Abstract] [Full Text] [PDF]

				G. C. Kane, A. Behfar, S. Yamada, C. Perez-Terzic, F. O'Cochlain, S. Reyes, P. P. Dzeja, T. Miki, S. Seino, and A. Terzic ATP-Sensitive K+ Channel Knockout Compromises the Metabolic Benefit of Exercise Training, Resulting in Cardiac Deficits Diabetes, December 1, 2004; 53(suppl_3): S169 - S175. [Abstract] [Full Text] [PDF]

				K. Minami, T. Miki, T. Kadowaki, and S. Seino Roles of ATP-Sensitive K+ Channels as Metabolic Sensors: Studies of Kir6.x Null Mice Diabetes, December 1, 2004; 53(suppl_3): S176 - S180. [Abstract] [Full Text] [PDF]

				L. Li, A. Rojas, J. Wu, and C. Jiang Disruption of Glucose Sensing and Insulin Secretion by Ribozyme Kir6.2-Gene Targeting in Insulin-Secreting Cells Endocrinology, September 1, 2004; 145(9): 4408 - 4414. [Abstract] [Full Text] [PDF]

				B. S. Bin-Abbas and A. A. Al-Ashwal Diabetes In A Nonpancreatectomized Child With Nesidioblastosis Diabetes Care, February 1, 2004; 27(2): 626 - 627. [Full Text] [PDF]

				T. Tsuboi, J. D. Lippiat, F. M. Ashcroft, and G. A. Rutter ATP-dependent interaction of the cytosolic domains of the inwardly rectifying K+ channel Kir6.2 revealed by fluorescence resonance energy transfer PNAS, January 6, 2004; 101(1): 76 - 81. [Abstract] [Full Text] [PDF]

				M. J. DUNNE, K. E. COSGROVE, R. M. SHEPHERD, A. AYNSLEY-GREEN, and K. J. LINDLEY Hyperinsulinism in Infancy: From Basic Science to Clinical Disease Physiol Rev, January 1, 2004; 84(1): 239 - 275. [Abstract] [Full Text] [PDF]

				R. Burcelin, B. Thorens, M. Glauser, R. C. Gaillard, and F. P. Pralong Gonadotropin-Releasing Hormone Secretion from Hypothalamic Neurons: Stimulation by Insulin and Potentiation by Leptin Endocrinology, October 1, 2003; 144(10): 4484 - 4491. [Abstract] [Full Text] [PDF]

				S. Le Gurun, D. Martin, A. Formenton, P. Maechler, D. Caille, G. Waeber, P. Meda, and J.-A. Haefliger Connexin-36 Contributes to Control Function of Insulin-producing Cells J. Biol. Chem., September 26, 2003; 278(39): 37690 - 37697. [Abstract] [Full Text] [PDF]

				J.-F. Rolland, J.-C. Henquin, and P. Gilon G Protein-independent Activation of an Inward Na+ Current by Muscarinic Receptors in Mouse Pancreatic beta -Cells J. Biol. Chem., October 4, 2002; 277(41): 38373 - 38380. [Abstract] [Full Text] [PDF]

				S. Srinivasan, E. Bernal-Mizrachi, M. Ohsugi, and M. A. Permutt Glucose promotes pancreatic islet beta -cell survival through a PI 3-kinase/Akt-signaling pathway Am J Physiol Endocrinol Metab, October 1, 2002; 283(4): E784 - E793. [Abstract] [Full Text] [PDF]

				G. Bertrand, N. Ishiyama, M. Nenquin, M. A. Ravier, and J.-C. Henquin The Elevation of Glutamate Content and the Amplification of Insulin Secretion in Glucose-stimulated Pancreatic Islets Are Not Causally Related J. Biol. Chem., August 30, 2002; 277(36): 32883 - 32891. [Abstract] [Full Text] [PDF]

				H. Huopio, S.-L. Shyng, T. Otonkoski, and C. G. Nichols KATP channels and insulin secretion disorders Am J Physiol Endocrinol Metab, August 1, 2002; 283(2): E207 - E216. [Abstract] [Full Text] [PDF]

				M.-J. Garcia-Barrado, M. A. Ravier, J.-F. Rolland, P. Gilon, M. Nenquin, and J.-C. Henquin Inhibition of Protein Synthesis Sequentially Impairs Distinct Steps of Stimulus-secretion Coupling in Pancreatic {beta} Cells Endocrinology, January 1, 2001; 142(1): 299 - 307. [Abstract] [Full Text] [PDF]