Abnormal Cardiac Na + Channel Properties and QT Heart Rate Adaptation in Neonatal Ankyrin B Knockout Mice

Abstract

—The cytoskeleton of the cardiomyocyte has been shown to modulate ion channel function. Cytoskeletal disruption in vitro alters Na⁺ channel kinetics, producing a late Na⁺ current that can prolong repolarization. This study describes the properties of the cardiac Na⁺ channel and cardiac repolarization in neonatal mice lacking ankyrin_B, a cytoskeletal “adaptor” protein. Using whole-cell voltage clamp techniques, I_Na density was lower in ankyrin_B(−/−) ventricular myocytes than in wild-type (WT) myocytes (−307±26 versus −444±39 pA/pF, PB(−/−) myocytes exhibited a hyperpolarizing shift in activation and inactivation kinetics compared with WT. Slower recovery from inactivation contributed to the negative shift in steady-state inactivation in ankyrin_B(−/−). Single Na⁺ channel mean open time was longer in ankyrin_B(−/−) versus WT at test potentials (V_t) of −40 mV (1.0±0.1 versus 0.61±0.04 ms, PPB(−/−) exhibited late single-channel openings at V_t −40 and −50 mV, which were not seen in WT. Late I_Na contributed to longer action potential durations measured at 90% repolarization (APD₉₀) at 1 Hz stimulation in ankyrin_B(−/−) compared with WT (354±26 versus 274±22 ms, PB(−/−) than in WT (380±14 versus 434±13 bpm, PB(−/−) and WT at physiological heart rates, QT-interval prolongation in response to heart rate deceleration was greater in ankyrin_B(−/−). In conclusion, Na⁺ channels in ankyrin_B(−/−) display reduced I_Na density and abnormal kinetics at the whole-cell and single-channel level that contribute to prolonged APD₉₀ and abnormal QT-rate adaptation.