Abstract
Inactivation of currents carried by Ba2+ and Ca$^2+$, as well
as intramembrane charge movement from L-type Ca$^2+$ channels
were studied in guinea pig ventricular myocytes using the whole-cell
patch clamp technique. Prolonged (2 s) conditioning depolarization
caused substantial reduction of charge movement between -70 and 10
mV (charge 1, or charge from noninactivated channels). In parallel,
the charge mobile between -70 and -150 mV (charge 2, or charge from
inactivated channels) was increased. The availability of charge 2
depended on the conditioning pulse voltage as the sum of two Boltzmann
components. One component had a central voltage of -75 mV and a magnitude
of 1.7 nC/microF. It presumably is the charge movement (charge 2)
from Na$^+$ channels. The other component, with a central voltage
of approximately -30 mV and a magnitude of 3.5 nC/microF, is the
charge 2 of L-type Ca$^2+$ channels. The sum of charge 1 and
charge 2 was conserved after different conditioning pulses. The difference
between the voltage dependence of the activation of L-type Ca$^2+$
channels (half-activation voltage, V, of approximately -20 mV) and
that of charge 2 (V of -100 mV) made it possible to record the ionic
currents through Ca$^2+$ channels and charge 2 in the same solution.
In an external solution with Ba2+ as sole metal the maximum available
charge 2 of L-type Ca$^2+$ channels was 10-15\% greater than
that in a Ca$^2+$-containing solution. External Cd2+ caused 20-30\%
reduction of charge 2 both from Na$^+$ and L-type Ca$^2+$
channels. Voltage- and Ca$^2+$-dependent inactivation phenomena
were compared with a double pulse protocol in cells perfused with
an internal solution of low calcium buffering capacity. As the conditioning
pulse voltage increased, inactivation monitored with the second pulse
went through a minimum at about 0 mV, the voltage at which conditioning
current had its maximum. Charge 2, recorded in parallel, did not
show any increase associated with calcium entry. Two alternative
interpretations of these observations are: (a) that Ca$^2+$-dependent
inactivation does not alter the voltage sensor, and (b) that inactivation
affects the voltage sensor, but only in the small fraction of channels
that open, and the effect goes undetected. A model of channel gating
that assumes the first possibility is shown to account fully for
the experimental results. Thus, extracellular divalent cations modulate
voltage-dependent inactivation of the Ca$^2+$ channel. Intracellular
Ca$^2+$ instead, appears to cause inactivation of the channel
without affecting its voltage sensor.
Description
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