Multimodal action of single Na+ channels in myocardial mouse cells

Bohle, Thomas; Benndorf, Klaus

doi:10.1016/s0006-3495(95)80166-9

Cited by 24 publications

(20 citation statements)

References 37 publications

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“…We looked for distinct Na ϩ -channel gating modes (F-mode, M1-mode, M2-mode, S-mode, and P-mode), which have previously been characterized in myocardial cells from adult white mice. 13 For this purpose, patches containing only a single Na ϩ channel were investigated. In previous studies, [13][14][15] gating modes were identified from the long time course of the averaged current per trace (average-of-interval plots).…”

Section: Discussionmentioning

confidence: 99%

“…13 For this purpose, patches containing only a single Na ϩ channel were investigated. In previous studies, [13][14][15] gating modes were identified from the long time course of the averaged current per trace (average-of-interval plots). There it was found that modal gating may happen in at least two different ways: (1) The lifetime of a specific mode may be rather long, ie, about some seconds to several minutes or (2) the lifetime of a specific mode may be rather short, ie, less than about a few seconds.…”

Section: Discussionmentioning

confidence: 99%

“…By using thick-walled patch pipettes 11 with ultraclean tips, 12 five distinct gating modes of Na ϩ -channel action (F-mode, M1-mode, M2-mode, S-mode, and P-mode) have been described in ventricular cells from adult white mice. [13][14][15] They differ at least in activation and/or inactivation kinetics, open-channel lifetime, and first latency. In the present report, we identified these gating modes in atrial and ventricular cells of normal and diseased human myocardium.…”

Section: A Lthough Namentioning

confidence: 99%

Section: Figure 2 Compares Single Namentioning

confidence: 99%

“…Macroscopic kinetics of the Na ϩ current are characteristic in each mode. 13,15 In the F-mode, fast activation is followed by fast inactivation; in the M1-mode, fast activation is followed by fast to intermediate inactivation; in the M2-mode, fast activation is followed by intermediate to slow inactivation; in the S-mode, fast activation is followed by slow inactivation; and in the P-mode, slow activation is followed by slow inactivation.The mode-specific kinetics of the currents were fitted with a Hodgkin-Huxley model of the type Am 3 h (see Materials and Methods for details). The magnitude of the parameters, activation-time constant ( m ) and inactivation-time constant ( h ), is indicated for each mode.…”

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Identification of Gating Modes in Single Native Na ⁺ Channels From Human Atrium and Ventricle

Bohle

Brandt

Lindner

et al. 2002

Circulation Research

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Abstract-The aim of the present study was to investigate the single-channel properties of different gating modes in the native human cardiac Na ϩ channel. Patch-clamp experiments were performed at low noise using ultrathick-walled pipettes. In 17 cell-attached patches containing only one channel, fast back and forth switching between five different Na ϩ -channel gating modes (F-mode, M1-mode, M2-mode, S-mode, and P-mode) was identified, but no difference in the gating properties was found between normal and diseased cardiomyocytes from atrium or ventricle, respectively. Hodgkin-Huxley fits to the ensemble-averaged currents yielded the activation-time ( m ) and inactivation-time ( h ) constants. m was comparably fast in the F-mode, M1-mode, M2-mode, and S-mode (0.15 ms) and slow in the P-mode (0.3 ms). h ranged from 0.35 ms (F-mode) to 4.5 ms (S-mode and P-mode). The mean open-channel lifetime ( o ) was shortest in the F-mode and P-mode (0.15 ms) and longest in the S-mode (1.25 ms). The time before which half of the first channel openings occurred (t 0.5 ) was comparably short in the F-mode, M1-mode, M2-mode, and S-mode (0.3 ms) and long in the P-mode (0.9 ms). It is concluded that (1) a single native human cardiac Na ϩ channel can be recorded at low noise, (2) this channel can change its gating properties at a time scale of milliseconds, (3) lifetimes of the observed gating modes are short ranging from milliseconds to seconds only, and (4) Key Words: patch clamp Ⅲ human myocardial sodium channels Ⅲ modal gating Ⅲ channel activation Ⅲ channel inactivation A lthough Na ϩ channels have been subject to intense electrophysiological investigation in various tissues, 1 little is known about the native human cardiac Na ϩ channel. Previously published studies have been conducted in heterologous expression systems, where channel proteins are removed from their physiological environment. [2][3][4] In these experiments, the Na ϩ channel ␣-subunit (hH1) was expressed alone, or coexpression with the ␤ 1 -subunit was performed. Other methods used the reconstituted Na ϩ -channel protein fused into planar lipid bilayers. 5 A major disadvantage of these methods is the artificial environment, in which electrophysiological experiments on the channel were performed. In the present study, results on single native human cardiac Na ϩ channels are presented. Our approach may lead to important insights into the physiological function of this channel protein.Using this approach, arrhythmias may be understood in more detail. It has been shown that the LQT3 syndrome and the Brugada syndrome are based on different mutations in the gene (SCN5A, 3p21) encoding for hH1. 6 -8 In heterologous expression systems, a distinct mutation (⌬KPQ) underlying the LQT3 syndrome is associated with late Na ϩ currents. 9 From fits of the results of these experiments to different kinetic models, it was postulated that modal gating of the channel protein may be the reason for the late currents. 9,10 Hence, genetic defects may underlie different rates of switch...

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