title: 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, P<0.01). Ankyrin(B)(-/-) 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, P<0.05) and -50 mV (0.8+/-0.1 versus 0.39+/-0.05 ms, P<0.05). Ankyrin(B)(-/-) 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 (APD(90)) at 1 Hz stimulation in ankyrin(B)(-/-) compared with WT (354+/-26 versus 274+/-22 ms, P<0.05). From ECG recordings of neonatal mice, heart rates were slower in ankyrin(B)(-/-) than in WT (380+/-14 versus 434+/-13 bpm, P<0.01). Although the QT interval was similar in ankyrin(B)(-/-) 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 APD(90) and abnormal QT-rate adaptation.
authors.affiliation: Division of Cardiology, Duke University Medical Center, Durham, NC 27710-3504, USA.
authors.forename: V S
authors.initials: VS
authors.lastname: Chauhan
authors.forename: S
authors.initials: S
authors.lastname: Tuvia
authors.forename: M
authors.initials: M
authors.lastname: Buhusi
authors.forename: V
authors.initials: V
authors.lastname: Bennett
authors.forename: A O
authors.initials: AO
authors.lastname: Grant
mesh_terms: D000200:Action Potentials; D000222:Adaptation, Physiological; D000818:Animals; D000831:Animals, Newborn / Q000502:physiology; D017487:Ankyrins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004562:Electrocardiography; D006339:Heart Rate; D008133:Long QT Syndrome / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018408:Patch-Clamp Techniques; D012016:Reference Values; D015222:Sodium Channels / Q000378:metabolism*
chemical_list: D017487:Ankyrins; D015222:Sodium Channels