© 2000 American Heart Association, Inc.
Cellular Biology |
Abnormal Cardiac Na+ Channel Properties and QT Heart Rate Adaptation in Neonatal AnkyrinB Knockout Mice
From the Division of Cardiology (V.S.C., A.O.G.), Duke University Medical Center, and Department of Cell Biology (S.T., M.B., V.B.), Howard Hughes Medical Institute, Durham, NC.
Correspondence to A.O. Grant, Duke University Medical Center, Box 3504, Durham, NC 27710-3504. E-mail aog{at}carlin.mc.duke.edu
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 ankyrinB, a cytoskeletal "adaptor" protein. Using whole-cell voltage clamp techniques, INa density was lower in ankyrinB(-/-) ventricular myocytes than in wild-type (WT) myocytes (-307±26 versus -444±39 pA/pF, P<0.01). AnkyrinB(-/-) 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 ankyrinB(-/-). Single Na+ channel mean open time was longer in ankyrinB(-/-) versus WT at test potentials (Vt) of -40 mV (1.0±0.1 versus 0.61±0.04 ms, P<0.05) and -50 mV (0.8±0.1 versus 0.39±0.05 ms, P<0.05). AnkyrinB(-/-) exhibited late single-channel openings at Vt -40 and -50 mV, which were not seen in WT. Late INa contributed to longer action potential durations measured at 90% repolarization (APD90) at 1 Hz stimulation in ankyrinB(-/-) compared with WT (354±26 versus 274±22 ms, P<0.05). From ECG recordings of neonatal mice, heart rates were slower in ankyrinB(-/-) than in WT (380±14 versus 434±13 bpm, P<0.01). Although the QT interval was similar in ankyrinB(-/-) and WT at physiological heart rates, QT-interval prolongation in response to heart rate deceleration was greater in ankyrinB(-/-). In conclusion, Na+ channels in ankyrinB(-/-) display reduced INa density and abnormal kinetics at the whole-cell and single-channel level that contribute to prolonged APD90 and abnormal QT-rate adaptation.
Key Words: Na+ channel • repolarization • transgenic mice • cytoskeleton • long-QT syndrome
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