© 1996 American Heart Association, Inc.
Articles |
Unitary Cl- Channels Activated by Cytoplasmic Ca2+ in Canine Ventricular Myocytes
From the Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno.
Correspondence to Dr J.R. Hume, Department of Physiology and Cell Biology/351, University of Nevada School of Medicine, Reno, NV 89557-0046.
Abstract Recent whole-cell studies have shown that
Ca2+-activated Cl- currents
contribute to the Ca2+-dependent
4-aminopyridine–insensitive component of the
transient outward current and to the arrhythmogenic transient inward
current in rabbit and canine cardiac cells. These
Cl--sensitive currents are activated by
Ca2+ release from the sarcoplasmic reticulum and are
inhibited by anion transport blockers; however, the unitary single
channels responsible have yet to be identified. We used inside-out
patches from canine ventricular myocytes and conditions
under which the only likely permeant ion is Cl- to
identify 4-aminopyridine–resistant unitary
Ca2+-activated Cl- channels.
Ca2+ applied to the cytoplasmic surface of membrane patches
activated small-conductance (1.0 to 1.3 pS) channels. These
channels were Cl- selective, with rectification
properties that could be described by the Goldman-Hodgkin-Katz current
equation. Channel activity exhibited time independence when cytoplasmic
Ca2+ was held constant and was blocked by the anion
transport blockers, DIDS and niflumic acid. Ca2+ (ranging
from pCa 
6 to pCa 3) applied to the cytoplasmic surface of
inside-out patches increased, in a dose-dependent manner,
NPo, where N is the number of channels opened and
Po is open probability. At negative membrane potentials
(-60 to -130 mV), an estimate of the dependence of
NPo on cytoplasmic Ca2+ yielded an apparent
Kd of 150.2 µmol/L. At pCa 3, an average
channel density of 
3 µm-2 was
estimated. Calculations based on these estimates of cytoplasmic
Ca2+ sensitivity and channel current amplitude and density
suggest that these small-conductance Cl- channels
contribute significant whole-cell membrane current in response to
changes in intracellular Ca2+ within the
physiological range. We suggest that these
small-conductance Ca2+-activated
Cl- channels underlie the transient
Ca2+-activated
4-aminopyridine–insensitive current, which
contributes to phase-1 repolarization, and under conditions of
Ca2+ overload, these channels may generate transient inward
currents, contributing to the development of triggered cardiac
arrhythmias.
Key Words: Ca2+-activated transient outward current • canine ventricles • cardiac electrophysiology • Cl- channels
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