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J Biol Chem, Vol. 275, Issue 11, 7811-7817, March 17, 2000
From the Department of Biology, Georgia State University,
Atlanta, Georgia 30302-4010
ROMK channels are inhibited by intracellular
acidification. This pH sensitivity is related to several amino acid
residues in the channel proteins such as Lys-61, Thr-51, and His-206
(in ROMK2). Unlike all other amino acids, histidine is titratable at pH
6-7 carrying a positive charge below pH 6. To test the hypothesis that
certain histidine residues are engaged in CO2 and pH
sensing of ROMK1, we performed experiments by systematic mutations of all histidine residues in the channel using the site-directed mutagenesis. There are two histidine residues in the N terminus. Mutations of His-23, His-31, or both together did not affect channel sensitivity to CO2. Six histidine residues are located in
the C terminus. His-225, His-274, His-342, and His-354 were critical in
CO2 and pH sensing. Mutation of either of them reduced
CO2 and pH sensitivities by 20-50% and ~0.2 pH units,
respectively. Simultaneous mutations of all of them eliminated the
CO2 sensitivity and caused this mutant channel to respond
to only extremely acidic pH. Similar mutations of His-280 had no
effect. The role of His-270 in CO2 and pH sensing is
unclear, because substitutions of this residue with either a neutral,
negative, or positive amino acid did not produce any functional
channel. These results therefore indicate that histidine residues
contribute to the sensitivity of the ROMK1 channel to hypercapnia and
intracellular acidosis.
Involvement of Histidine Residues in Proton Sensing of ROMK1
Channel*
*
This work was supported by National Institutes of Health
Grant HL58410-01 and the Grant-in-Aid Award 9950528N from the American Heart Association.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 Biology,
Georgia State University, 24 Peachtree Central Ave., Atlanta, GA
30303-4010. Tel.: 404-651-0913; Fax: 404-651-2509; E-mail: biocjj@panther.gsu.edu.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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