© 1999 by European Society of Cardiology
Copyright © 1999, European Society of Cardiology
β-adrenergic action on wild-type and KPQ mutant human cardiac Na+ channels: shift in gating but no change in Ca2+: Na+ selectivity
aDuke University Medical Center, Durham, NC, USA
bMedical University of South Carolina, Charleston, SC, USA
aog{at}carlin.mc.duke.edu
* Corresponding author. Tel.: +1-919-684-3901; fax: +1-919-681-8978
Objective: Prior studies of the modulation of the Na+ current by sympathetic stimulation have yielded controversial results. Separation of the Na+ and Ca2+ currents poses a problem in myocyte preparations. The gating of cloned Na+ channels is different in oocytes compared with mammalian expression systems. We have examined the sympathetic modulation of the 
-subunit of the wild-type human cardiac Na+ channel (hH1) and the long QT-associated mutant, 
KPQ, expressed in human embryonic kidney cells. Methods: Stable cell lines of hH1 and KPQ were established in human embryonic kidney cells. Whole-cell and single-channel currents were measured with the patch–clamp technique. Sympathetic stimulation was effected by exposure to isoproterenol or 8-bromo-cAMP. Na+ channel activation and inactivation were determined using standard voltage clamp protocols. Ca2+: Na+ permeability ratio was determined under bi-ionic conditions. Results: We observed a qualitatively different effect of sympathetic stimulation on the cardiac Na+ current from that reported in frog oocytes: activation and inactivation kinetics were shifted to more negative potentials. This shift was similar for both hH1 and KPQ. [V0.5 for inactivation: 8.3±1.7 mV, p<0.001 (hH1); 6.8±0.9 mV, p<0.001 (KPQ)]. Increased rate of closed-state inactivation contributed to the shifting of the inactivation–voltage relationship. Open-state inactivation was not affected as mean open times were unchanged. Reversal potential measurement in hH1 suggested a low Ca2+: Na+ permeability ratio of 0.017, uninfluenced by sympathetic stimulation. In KPQ, the size of the persistent relative to the peak current was increased with 8-bromo-cAMP from 3.0±0.7% to 4.3±0.6% (p=0.056). Conclusions: Sympathetic stimulation exerts multiple effects on the gating of hH1. Similar effects are also seen in KPQ which may increase arrhythmia susceptibility in long QT syndrome by modifying the Na+ channel contribution to the action potential.
KEYWORDS Na-channel; Long QT syndrome; Adrenergic agonists; Single-channel currents; Membrane permeability
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