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J. Biol. Chem., Vol. 277, Issue 40, 37105-37115, October 4, 2002
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From the Recently, we reported that mutation
A1529D in the domain (D) IV P-loop of the rat skeletal muscle
Na+ channel µ1 (DIV-A1529D) enhanced
entry to an inactivated state from which the channels recovered with an
abnormally slow time constant on the order of ~100 s. Transition to
this "ultra-slow" inactivated state (USI) was substantially reduced
by binding to the outer pore of a mutant µ-conotoxin GIIIA. This
indicated that USI reflected a structural rearrangement of the outer
channel vestibule and that binding to the pore of a peptide could
stabilize the pore structure (Hilber, K., Sandtner, W.,
Kudlacek, O., Glaaser, I. W., Weisz, E., Kyle, J. W., French,
R. J., Fozzard, H. A., Dudley, S. C., and Todt, H. (2001) J. Biol. Chem. 276, 27831-27839). Here, we
tested the hypothesis that occlusion of the inner vestibule of the
Na+ channel by the fast inactivation gate inhibits
ultra-slow inactivation. Stabilization of the fast inactivated state
(FI) by coexpression of the rat brain
Interaction between Fast and Ultra-slow Inactivation in the
Voltage-gated Sodium Channel
DOES THE INACTIVATION GATE STABILIZE THE CHANNEL STRUCTURE?*
§,§,,,,
, and**
Institute of Pharmacology, University of
Vienna, A-1090 Vienna, Austria, the ¶ Cardiac Electrophysiology
Laboratories, The University of Chicago, Chicago, Illinois 60637, and
the Division of Cardiology, Emory University, Atlanta, Georgia
30033 and the Atlanta Veterans Affairs Hospital,
Decatur, Georgia 30033
1 subunit in
Xenopus oocytes significantly prolonged the time course of
entry to the USI. A reduction in USI was also observed when the FI was
stabilized in the absence of the 1 subunit, suggesting a
causal relation between the occurrence of the FI and inhibition of USI.
This finding was further confirmed in experiments where the FI was
destabilized by introducing the mutations I1303Q/F1304Q/M1305Q. In
DIV-A1529D + I1303Q/F1304Q/M1305Q channels, occurrence of USI was
enhanced at strongly depolarized potentials and could not be prevented
by coexpression of the 1 subunit. These results strongly
suggest that FI inhibits USI in DIV-A1529D channels. Binding to the
inner pore of the fast inactivation gate may stabilize the channel
structure and thereby prevent USI. Some of the data have been published
previously in abstract form (Hilber, K., Sandtner, W., Kudlacek, O.,
Singer, E., and Todt, H. (2002) Soc. Neurosci. Abstr. 27, program number 46.12).
*
This work was supported by Fonds zur Förderung der
Wissenschaftlichen Forschung Grant P13961-MED (to H. T.), by National Institutes of Health Grant HL-P01-20592 (to H. A. F.), by an
American Heart Association Southeast Affiliate Beginning grant-in-aid
(to S. C. D.), by a Scientist Development Award from the American Heart Association, by a Procter and Gamble University Research Exploratory Award, and by National Institutes of Health Grant HL64828.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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