title: Abnormal Na channel gating in murine cardiac myocytes deficient in myotonic dystrophy protein kinase.
abstract: DMPK is a serine/threonine kinase implicated in the human disease myotonic muscular dystrophy (DM). Skeletal muscle Na channels exhibit late reopenings 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 reopenings occurring after the macroscopic Na current had subsided in both Dmpk+/- and Dmpk-/- muscle, but only rare reopenings 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 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 reopenings 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.
authors.affiliation: Department of Biomedical Engineering, University of Virginia Health Systems, Charlottesville, Virginia 22908, USA.
authors.forename: Hwa C
authors.initials: HC
authors.lastname: Lee
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Patel
authors.forename: Dilawaar J
authors.initials: DJ
authors.lastname: Mistry
authors.forename: Qingcai
authors.initials: Q
authors.lastname: Wang
authors.forename: Sita
authors.initials: S
authors.lastname: Reddy
authors.forename: J Randall
authors.initials: JR
authors.lastname: Moorman
authors.forename: J Paul
authors.initials: JP
authors.lastname: Mounsey
mesh_terms: D000200:Action Potentials / Q000235:genetics; D000818:Animals; D020296:Animals, Congenic; D015640:Ion Channel Gating / Q000235:genetics*; D008564:Membrane Potentials / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000737:chemistry / Q000201:enzymology* / Q000378:metabolism*; D009223:Myotonic Dystrophy / Q000235:genetics; D065636:Myotonin-Protein Kinase; D018408:Patch-Clamp Techniques; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics*; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism / Q000502:physiology
chemical_list: C585517:DMPK protein, human; C585516:DMPK protein, mouse; D015222:Sodium Channels; D065636:Myotonin-Protein Kinase; D017346:Protein Serine-Threonine Kinases