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Rundown and reactivation of ATP-sensitive potassium channels (KATP) in mouse skeletal muscle

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Abstract

Dissociated single fibers from the mouse flexor digitorum brevis (FDB) muscle were used in patch clamp experiments to investigate the mechanisms of activation and inactivation of KATP in mammalian skeletal muscle. Spontaneous rundown of channel activity, in many excised patches, occurred gradually over a period of 10–20 min. Application of 1.0 mm free-Ca2+ to the cytoplasmic side of the patch caused irreversible inactivation of KATP within 15 sec. Ca2+-induced rundown was not prevented by the presence of 1.0 μm okadaic acid or 2.0 mg ml− of an inhibitor of calcium-activated neutral proteases, a result consistent with the conclusion that phosphatases or calcium-activated neutral proteases were not involved in the rundown process. Application of 1.0 mm Mg.ATP to Ca2+inactivated KATP caused inhibition of residual activity but little or no reactivation of the channels upon washout of ATP, even in the presence of the catalytic subunit of cyclic AMP-dependent protein kinase (10 U ml−1). Mg.ATP also failed to reactivate KATP, even after only partial spontaneous rundown, despite the presence of channels that could be activated by the potassium channel opener BRL 38227. Nucleotide diphosphates (500 μm; CDP, UDP, GDP and IDP) caused immediate and reversible opening of Ca2+-inactivated KATP. Reactivation of KATP by ADP (100 μm) increased further upon removal of the nucleotide. In contrast to KATP from cardiac and pancreatic cells, there was no evidence for phosphorylation of KATP from the surface sarcolemma of dissociated single fibers from mouse skeletal muscle. The small degree of activation occasionally observed following application of 10 μm or 1.0 mm Mg.ATP could have been due to the generation of ADP from ATP hydrolysis and not through phosphorylation. Data are consistent with the suggestion that Ca2+ inactivation of KATP involves a gating mechanism that can be reopened by nucleotide diphosphates.

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  1. M. Hussain

    Present address: Department of Physiology, University of Leeds, The Worsley Medical and Dental Building, LS2 9NQ, Leeds, UK

Authors and Affiliations

  1. Division of Neuroscience, School of Biological Sciences, University of Manchester, Oxford Road, M13 9PT, Manchester, UK

    M. Hussain & A. C. Wareham

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  1. M. Hussain
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  2. A. C. Wareham
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M.H. is supported by the Medical Research Council.

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Hussain, M., Wareham, A.C. Rundown and reactivation of ATP-sensitive potassium channels (KATP) in mouse skeletal muscle. J. Membarin Biol. 141, 257–265 (1994). https://doi.org/10.1007/BF00235135

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  • DOI: https://doi.org/10.1007/BF00235135

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