Abnormal sodium channel gating in murine cardiac myocytes deficient in myotonic dystrophy protein kinase

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. Resting membrane and action potentials were similar in wild-type and Dmpk-deficient muscle. Macroscopic Na+ current density was also similar, as was steady-state Na+ channel gating and gating kinetics. We conclude that DMPK regulates cardiac Na+ channels. As in skeletal muscle, cardiac Na+ channels exhibit late re-openings with Dmpk-deficiency. In contrast to skeletal muscle, macroscopic cardiac Na+ currents are unaffected by Dmpk-deficiency. The persistent Na + current we observe, if translated to human DM, could account for both the heart block and ventricular tachycardia characteristic of the disease.