HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sakura, H. Articles by Ashcroft, F. M. Search for Related Content PubMed PubMed Citation Articles by Sakura, H. Articles by Ashcroft, F. M.

Altered functional properties of K_ATP channel conferred by a novel splice variant of SUR1

Hiroshi Sakura, Stefan Trapp, Birgit Liss and Frances M. Ashcroft

ATP-sensitive potassium (K_ATP) channels are composed of pore-forming (Kir6.x) and regulatory sulphonylurea receptor (SURx) subunits. We have isolated a novel SUR variant (SUR1b33) from a hypothalamic cDNA library. This variant lacked exon 33 and introduced a frameshift that produced a truncated protein lacking the second nucleotide binding domain (NBD2). It was expressed at low levels in hypothalamus, midbrain, heart and the insulin-secreting -cell line MIN6.

We examined the properties of K_ATP channels composed of Kir6.2 and SUR1b33 by recording macroscopic currents in membrane patches excised from Xenopus oocytes expressing these subunits. We also investigated the effect of truncating SUR1 at either the start (SUR1bT1) or end (SUR1bT2) of exon 33 on K_ATP channel properties.

Kir6.2/SUR1b33 showed an enhanced open probability (P_o = 0·6 at -60 mV) and a reduced ATP sensitivity (K_i, 86 µM), when compared with wild-type channels (P_o = 0·3; K_i, 22 µM). However, Kir6.2/SUR1bT1 and Kir6.2/SUR1bT2 resembled the wild-type channel in their P_o and ATP sensitivity.

Neither MgADP, nor the K⁺ channel opener diazoxide, enhanced Kir6.2/SUR1b33, Kir6.2/SUR1bT1 or Kir6.2/SUR1bT2 currents, consistent with the idea that these agents require an intact NBD2 for their action. Sulphonylureas blocked K_ATP channels containing any of the three SUR variants, but in excised patches the extent of block was less than that for the wild-type channel. In intact cells, the extent of sulphonylurea block of Kir6.2/SUR1b33 was greater than that in excised patches and was comparable to that found for wild-type channels.

Our results demonstrate that NBD2 is not essential for functional expression or sulphonylurea block, but is required for K_ATP channel activation by K⁺ channel openers and nucleotides. Some of the unusual properties of Kir6.2/SUR1b33 resemble those reported for the K_ATP channel of ventromedial hypothalamic (VMH) neurones, but the fact that this mRNA is expressed at low levels in many other tissues makes it less likely that SUR1b33 serves as the SUR subunit for the VMH K_ATP channel.

This article has been cited by other articles:

				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]

				P. Proks, F. Reimann, N. Green, F. Gribble, and F. Ashcroft Sulfonylurea Stimulation of Insulin Secretion Diabetes, December 1, 2002; 51(90003): S368 - 376. [Abstract] [Full Text] [PDF]

				A. P. Babenko and J. Bryan SUR-dependent Modulation of KATP Channels by an N-terminal KIR6.2 Peptide. DEFINING INTERSUBUNIT GATING INTERACTIONS J. Biol. Chem., November 8, 2002; 277(46): 43997 - 44004. [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]

				A. Hambrock, R. Preisig-Muller, U. Russ, A. Piehl, P. J. Hanley, J. Ray, J. Daut, U. Quast, and C. Derst Four novel splice variants of sulfonylurea receptor 1 Am J Physiol Cell Physiol, August 1, 2002; 283(2): C587 - C598. [Abstract] [Full Text] [PDF]

				J. P. Giblin, Y. Cui, L. H. Clapp, and A. Tinker Assembly Limits the Pharmacological Complexity of ATP-sensitive Potassium Channels J. Biol. Chem., April 12, 2002; 277(16): 13717 - 13723. [Abstract] [Full Text] [PDF]

				R. Burcelin and B. Thorens Evidence That Extrapancreatic GLUT2-Dependent Glucose Sensors Control Glucagon Secretion Diabetes, June 1, 2001; 50(6): 1282 - 1289. [Abstract] [Full Text]

				C. Hernández-Sánchez, A. S. Basile, I. Fedorova, H. Arima, B. Stannard, A. M. Fernandez, Y. Ito, and D. LeRoith Mice transgenically overexpressing sulfonylurea receptor 1 in forebrain resist seizure induction and excitotoxic neuron death PNAS, February 22, 2001; (2001) 51012898. [Abstract] [Full Text]

				F. C. Schuit, P. Huypens, H. Heimberg, and D. G. Pipeleers Glucose Sensing in Pancreatic {beta}-Cells: A Model for the Study of Other Glucose-Regulated Cells in Gut, Pancreas, and Hypothalamus Diabetes, January 1, 2001; 50(1): 1 - 11. [Abstract] [Full Text]

				C. Hernandez-Sanchez, A. S. Basile, I. Fedorova, H. Arima, B. Stannard, A. M. Fernandez, Y. Ito, and D. LeRoith Mice transgenically overexpressing sulfonylurea receptor 1 in forebrain resist seizure induction and excitotoxic neuron death PNAS, March 13, 2001; 98(6): 3549 - 3554. [Abstract] [Full Text] [PDF]