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Biophys J, May 1999, p. 2530-2552, Vol. 76, No. 5
Program in Molecular and Cellular Systems Physiology, Departments of Biomedical Engineering and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 USA
N-type calcium channels inactivate most rapidly in
response to moderate, not extreme depolarization. This behavior
reflects an inactivation rate that bears a U-shaped dependence on
voltage. Despite this apparent similarity to calcium-dependent
inactivation, N-type channel inactivation is insensitive to the
identity of divalent charge carrier and, in some reports, to the level
of internal buffering of divalent cations. Hence, the inactivation of
N-type channels fits poorly with the "classic" profile for either
voltage-dependent or calcium-dependent inactivation. To investigate
this unusual inactivation behavior, we expressed recombinant N-type
calcium channels in mammalian HEK 293 cells, permitting in-depth
correlation of ionic current inactivation with potential alterations of
gating current properties. Such correlative measurements have been
particularly useful in distinguishing among various inactivation
mechanisms in other voltage-gated channels. Our main results are the
following: 1) The degree of gating charge immobilization was unchanged
by the block of ionic current and precisely matched by the extent of
ionic current inactivation. These results argue for a purely
voltage-dependent mechanism of inactivation. 2) The inactivation rate
was fastest at a voltage where only ~
of the total gating
charge had moved. This unusual experimental finding implies that
inactivation occurs most rapidly from intermediate closed conformations
along the activation pathway, as we demonstrate with novel analytic
arguments applied to coupled-inactivation schemes. These results
provide strong, complementary support for a "preferential
closed-state" inactivation mechanism, recently proposed on the basis
of ionic current measurements of recombinant N-type channels (Patil et
al., 1998. Neuron. 20:1027-1038).
Biophys J, May 1999, p. 2530-2552, Vol. 76, No. 5
© 1999 by the Biophysical Society 0006-3495/99/05/2530/23 $2.00
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