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Articles in PresS, published online ahead of print November 26, 2002
Physiol Genomics, 10.1152/physiolgenomics.00095.2002
Submitted on July 30, 2002
Accepted on November 22, 2002
1 Biomedical Engineering, University of Virginia, Charlottesvile, VA, USA; The Cardiovascular Rearch Center, University of Virginia, Charlottesville, VA, USA
2 Internal Medicine (Cardiovascular Division), University of Virginia, Charlottesville, VA, USA
3 Institute of Genetic Medicine, University of Southern California, Los Angeles, CA, USA
4 Internal Medicine (Cardiovascular Division), University of Virginia, Charlottesville, VA, USA; Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA, USA; The Cardiovascular Rearch Center, University of Virginia, Charlottesville, VA, USA
5 Internal Medicine (Cardiovascular Division), University of Virginia, Charlottesville, VA, USA; The Cardiovascular Rearch Center, University of Virginia, Charlottesville, VA, USA
* To whom correspondence should be addressed. E-mail: pmounsey{at}virginia.edu.
DMPK is a serine/threonine kinase implicated in the human disease myotonic muscular dystrophy (DM). Skeletal muscle Na channels exhibit late re-openings in Dmpk-deficient mice and peak current density is reduced, implicating DMPK in regulation of membrane excitability. Since complete heart block and sudden cardiac death occur in the disease, we tested the hypothesis that cardiac Na channels also exhibit abnormal gating in Dmpk-deficient mice. We made whole-cell and cell-attached patch clamp recordings of ventricular cardiomyocytes enzymatically isolated from wild-type, Dmpk+/- and Dmpk-/- mice. Recordings from membrane patches containing one or a few Na channels revealed multiple Na channel re-openings occurring after the macroscopic Na current had subsided in both Dmpk+/- and Dmpk-/- muscle, but only rare re-openings in wild-type muscle (>3 fold difference, p<0.05). This resulted in a plateau of non-inactivating Na current in Dmpk-deficient muscle. The magnitude of this plateau current was independent on the magnitude of the test potential from -40 mV to 0 mV, and was also independent of gene dose. Macroscopic Na current density was similar in wild-type and Dmpk-deficient muscle, as was steady-state Na channel gating. Decay of macroscopic currents was slowed in Dmpk-/- muscle, but not in Dmpk+/- or wild-type muscle. Entry into, and recovery from, inactivation were similar at multiple test potentials in wild type and Dmpk-deficient muscle. Resting membrane potential was depolarized, and action potential duration was significantly prolonged in Dmpk-deficient muscle. Thus in cardiac muscle, Dmpk-deficiency results in multiple late re-openings of Na channels similar to those seen in Dmpk-deficient skeletal muscle. This is reflected in a plateau of non-inactivating macroscopic Na current and prolongation of cardiac action potentials.
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