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J Biol Chem, Vol. 275, Issue 7, 4928-4936, February 18, 2000
From the Department of Pathology, Anatomy and Cell Biology,
Jefferson Medical College, Philadelphia, Pennsylvania 19107
The structural bases of general anesthetic action
on a neuronal K+ channel were investigated using the
series of homologous 1-alkanols, electrophysiology, and mutational
analysis. Domain swapping between dShaw2 (alkanol-sensitive) and hKv3.4
(alkanol-resistant) and site-directed mutagenesis demonstrated that a
13-amino acid cytoplasmic loop (S4-S5) determines the selective
inhibition of native dShaw2 channels by 1-alkanols. The S4-S5 loop may
contribute to a receptor for both 1-alkanols and the inactivation
particle, because the enhanced 1-alkanol sensitivity of hKv3.4 channels
hosting S4-S5 mutations correlates directly with disrupted channel
inactivation. Evidence of a discrete protein site was also obtained
from the analysis of the relationship between potency and alkyl chain
length, which begins to level off after 1-hexanol. Rapid application to the cytoplasmic side of inside-out membrane patches shows that the
interaction between dShaw2 channels and 1-alkanols equilibrates in
<200 ms. By contrast, the equilibration time is >1000-fold slower
when the drug is applied externally to outside-out membrane patches.
The data strongly favor a mechanism of inhibition involving a discrete
internal site for 1-alkanols in dShaw2 K+ channels. A new
working hypothesis proposes that 1-alkanols lock dShaw2 channels in
their closed conformation by a direct interaction at a crevice formed
by the S4-S5 loop.
General Anesthetic Action at an Internal Protein Site
Involving the S4-S5 Cytoplasmic Loop of a Neuronal K+
Channel*
*
This work was supported by National Institutes of Health
Grant AA10615.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.
To whom correspondence should be addressed: Dept. of Pathology,
Anatomy and Cell Biology, Jefferson Medical College, 1020 Locust St.,
Philadelphia, PA 19107. Tel.: 215-503-4341; Fax: 215-923-2218; E-mail:
manuel.covarrubias@mail.tju.edu.
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