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) All Versions of this Article: 547/1/159    most recent 2002.031625v1 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 Reimann, F. Articles by Ashcroft, F. M. Search for Related Content PubMed PubMed Citation Articles by Reimann, F. Articles by Ashcroft, F. M.

Analysis of the differential modulation of sulphonylurea block of -cell and cardiac ATP-sensitive K⁺ (K_ATP) channels by Mg-nucleotides

Frank Reimann*†, Michael Dabrowski*, Phillippa Jones*, Fiona M. Gribble† and Frances M. Ashcroft*

Sulphonylureas stimulate insulin secretion by binding with high-affinity to the sulphonylurea receptor (SUR) subunit of the ATP-sensitive potassium (K_ATP) channel and thereby closing the channel pore (formed by four Kir6.2 subunits). In the absence of added nucleotides, the maximal block is around 60-80 %, indicating that sulphonylureas act as partial antagonists. Intracellular MgADP modulated sulphonylurea block, enhancing inhibition of Kir6.2/SUR1 (-cell type) and decreasing that of Kir6.2/SUR2A (cardiac-type) channels. We examined the molecular basis of the different response of channels containing SUR1 and SUR2A, by recording currents from inside-out patches excised from Xenopus oocytes heterologously expressing wild-type or chimeric channels. We used the benzamido derivative meglitinide as this drug blocks Kir6.2/SUR1 and Kir6.2/SUR2A currents, reversibly and with similar potency. Our results indicate that transfer of the region containing transmembrane helices (TMs) 8-11 and the following 65 residues of SUR1 into SUR2A largely confers a SUR1-like response to MgADP and meglitinide, whereas the reverse chimera (SUR128) largely endows SUR1 with a SUR2A-type response. This effect was not specific for meglitinide, as tolbutamide was also unable to prevent MgADP activation of Kir6.2/SUR128 currents. The data favour the idea that meglitinide binding to SUR1 impairs either MgADP binding or the transduction pathway between the NBDs and Kir6.2, and that TMs 8-11 are involved in this modulatory response. The results provide a basis for understanding how -cell K_ATP channels show enhanced sulphonylurea inhibition under physiological conditions, whereas cardiac K_ATP channels exhibit reduced block in intact cells, especially during metabolic inhibition.

This article has been cited by other articles:

				A. B. Karger, S. Park, S. Reyes, M. Bienengraeber, R. B. Dyer, A. Terzic, and A. E. Alekseev Role for SUR2A ED Domain in Allosteric Coupling within the KATP Channel Complex J. Gen. Physiol., February 25, 2008; 131(3): 185 - 196. [Abstract] [Full Text] [PDF]

				M. Winkler, D. Stephan, S. Bieger, P. Kuhner, F. Wolff, and U. Quast Testing the Bipartite Model of the Sulfonylurea Receptor Binding Site: Binding of A-, B-, and A + B-Site Ligands J. Pharmacol. Exp. Ther., August 1, 2007; 322(2): 701 - 708. [Abstract] [Full Text] [PDF]

				R. D. Rainbow, D. Lodwick, D. Hudman, N. W. Davies, R. I. Norman, and N. B. Standen SUR2A C-terminal fragments reduce KATP currents and ischaemic tolerance of rat cardiac myocytes J. Physiol., June 15, 2004; 557(3): 785 - 794. [Abstract] [Full Text] [PDF]

				G. C Rodrigo, N. W Davies, and N. B Standen Diazoxide causes early activation of cardiac sarcolemmal KATP channels during metabolic inhibition by an indirect mechanism Cardiovasc Res, February 15, 2004; 61(3): 570 - 579. [Abstract] [Full Text] [PDF]