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MOLECULAR AND GENOMIC |
1 Greenberg Division of Cardiology, Department of Medicine
2 Department of Pharmacology, Cornell University, Weill Medical College, 520 East 70th Street, New York, NY 10021, USA
3 The Parkinson's and Movement Disorder Research Laboratory, Long Beach Memorial Medical Center, 2625 Pasadena Avenue, Long Beach, CA 90806, USA
KCNQ1 
subunits form functionally distinct potassium channels by coassembling with KCNE ancillary subunits MinK and MiRP2. MinK-KCNQ1 channels generate the slowly activating, voltage-dependent cardiac IKs current. MiRP2-KCNQ1 channels form a constitutively active current in the colon. The structural basis for these contrasting channel properties, and the mechanisms of subunit modulation by KCNE subunits, are not fully understood. Here, scanning mutagenesis located a tryptophan-tolerant region at positions 338–340 within the KCNQ1 pore-lining S6 domain, suggesting an exposed region possibly amenable to interaction with transmembrane ancillary subunits. This hypothesis was tested using concomitant mutagenesis in KCNQ1 and in the membrane-localized ‘activation triplet’ regions of MinK and MiRP2 to identify pairs of residues that interact to control KCNQ1 activation. Three pairs of mutations exerted dramatic effects, ablating channel function or either removing or restoring control of KCNQ1 activation. The results place KCNE subunits close to the KCNQ1 pore, indicating interaction of MiRP2-72 with KCNQ1-338; and MinK-59,58 with KCNQ1-339, 340. These data are consistent either with perturbation of the S6 domain by MinK or MiRP2, dissimilar positioning of MinK and MiRP2 within the channel complex, or both. Further, the results suggest specifically that two of the interactions, MiRP2-72/KCNQ1-338 and MinK-58/KCNQ1-340, are required for the contrasting gating effects of MinK and MiRP2.
(Received 24 October 2005;
accepted after revision 17 November 2005;
first published online 24 November 2005)
Corresponding author G. W. Abbott: Starr 463, Greenberg Division of Cardiology, Weill Medical College of Cornell University, 520 East 70th Street, New York, NY 10021, USA. Email: gwa2001{at}med.cornell.edu
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