Reduced expression of Kir6.2/SUR2A subunits explains KATP deficiency in K+-depleted rats

Tricarico, Domenico; Mele, Antonietta; Liss, Birgit; Ashcroft, Frances M.; Lundquist, Andrew L.; Desai, Reshma R.; George, Alfred L.; Conte Camerino, Diana

doi:10.1016/j.nmd.2007.07.009

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Volume 18, Issue 1 , Pages 74-80, January 2008

Reduced expression of Kir6.2/SUR2A subunits explains K_ATP deficiency in K⁺-depleted rats

Domenico Tricarico
- Department of Pharmacobiology, Faculty of Pharmacy, University of Bari, via Orabona n° 4, 70120 Bari, Italy
- Corresponding author. Tel.: +39 0805442802; fax:+39 0805442801.
Antonietta Mele
- Department of Pharmacobiology, Faculty of Pharmacy, University of Bari, via Orabona n° 4, 70120 Bari, Italy
Birgit Liss
- Department of General Physiology, Molecular Neurophysiology, University of Ulm, Albert Einsteinalle 11, 89081 Ulm, Germany
Frances M. Ashcroft
- University Laboratory of Physiology, Parks Road, Oxford OX1 3PT, UK
Andrew L. Lundquist
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University, 529 Light Hall, Nashville, TN 37232-0275, USA
Reshma R. Desai
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University, 529 Light Hall, Nashville, TN 37232-0275, USA
Alfred L. George Jr.
- Division of Genetic Medicine, Department of Medicine, Vanderbilt University, 529 Light Hall, Nashville, TN 37232-0275, USA
Diana Conte Camerino
- Department of Pharmacobiology, Faculty of Pharmacy, University of Bari, via Orabona n° 4, 70120 Bari, Italy

Received 18 January 2007; received in revised form 17 May 2007; accepted 25 July 2007.

Abstract

We investigated on the mechanism responsible for the reduced ATP-sensitive K⁺(K_ATP) channel activity recorded from skeletal muscle of K⁺-depleted rats. Patch-clamp and gene expression measurements of K_ATP channel subunits were performed. A down-regulation of the K_ATP channel subunits Kir6.2(−70%) and SUR2A(−46%) in skeletal muscles of K⁺-depleted rats but no changes in the expression of Kir6.1, SUR1 and SUR2B subunits were observed. A reduced K_ATP channel currents of −69.5% in K⁺-depleted rats was observed. The Kir6.2/SUR2A-B agonist cromakalim showed similar potency in activating the K_ATP channels of normokalaemic and K⁺-depleted rats but reduced efficacy in K⁺-depleted rats. The Kir6.2/SUR1-2B agonist diazoxide activated K_ATP channels in normokalaemic and K⁺-depleted rats with equal potency and efficacy. The down-regulation of the Kir6.2 explains the reduced K_ATP channel activity in K⁺-depleted rats. The lower expression of SUR2A explains the reduced efficacy of cromakalim; preserved SUR1 expression accounts for the efficacy of diazoxide. Kir6.2/SUR2A deficiency is associated with impaired muscle function in K⁺-depleted rats and in hypoPP.