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J Biol Chem, Vol. 275, Issue 2, 1137-1144, January 14, 2000
From the Departments of Inwardly rectifying K+ currents
are generated by a complex of four Kir (Kir1-6) subunits. Pore
properties are conferred by the second transmembrane domain (M2) of
each subunit. Using cadmium ions as a cysteine-interacting probe, we
examined the accessibility of substituted cysteines in M2 of the Kir6.2
subunit of inwardly rectifying KATP channels. The ability
of Cd2+ ions to inhibit channels was used as the estimate
of accessibility. The distribution of Cd2+ accessibility is
consistent with an
Structure and Dynamics of the Pore of Inwardly Rectifying
KATP Channels*
§,§,
Cell Biology and Physiology
and ¶ Biochemistry and Molecular Biophysics, Washington University
School of Medicine, St. Louis, Missouri 63110
-helical structure of M2. The apparent surface of
reactivity is broad, and the most reactive residues correspond to the
solvent-accessible residues in the bacterial KcsA channel crystal
structure. In several mutants, single channel measurements indicated
that inhibition occurred by a single transition from the open state to
a zero-conductance state. Analysis of currents expressed from mixtures
of control and L164C mutant subunits indicated that at least three
cysteines are required for coordination of the Cd2+ ion.
Application of phosphatidylinositol 4,5-diphosphate to inside-out membrane patches stabilized the open state of all mutants and also
reduced cadmium sensitivity. Moreover, the Cd2+ sensitivity
of several mutants was greatly reduced in the presence of inhibitory
ATP concentrations. Taken together, these results are consistent with
state-dependent accessibility of single Cd2+
ions to coordination sites within a relatively narrow inner vestibule.
*
This work was supported by Grant HL54171 from the National
Institutes of Health (to C. G. N.); by a fellowship from the American Heart Association, Missouri Affiliate, and a grant from the Philippe Fondation, Paris, France (to G. L.); and by the Washington University Diabetes Research Training Center.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 and reprint requests should be
addressed: Dept. of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Ave., St. Louis, MO 63110. Tel.:
314-362-6630; Fax: 314-362-7463; E-mail:
cnichols@cellbio.wustl.edu.
1 The abbreviations used are: PIP2, phosphatidylinositol 4,5-diphosphate; MTSEA, (2-aminoethyl)methane thiosulfonate; MTS, methane thiosulfonate.
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