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Am J Physiol Cell Physiol (September 21, 2001). doi:10.1152/ajpcell.00232.2001
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Articles in PresS, published online ahead of print September 21, 2001
Am J Physiol Cell Physiol, 10.1152/ajpcell.00232.2001
Submitted on May 29, 2001
Accepted on September 17, 2001

Mutations throughout the S6 region of the hKv1.5 channel alter the stability of the activation gate

Thomas C Rich1, Sarita W Yeola2, Michael M Tamkun3, and Dirk J Snyders4*

1 Biomedical Engineering, Vanderbilt University, Nashville, TN, USA
2 Pharmacology, Vanderbilt University, Nashville, TN, USA
3 Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA; Pharmacology, Vanderbilt University, Nashville, TN, USA
4 Medicine, Vanderbilt University, Nashville, TN, USA; Pharmacology, Vanderbilt University, Nashville, TN, USA

* To whom correspondence should be addressed. E-mail: thomas.rich{at}UCHSC.edu.

The S6 segment of voltage-gated K+ channels is thought to contribute to the gate that opens the central permeation pathway. Here we present evidence that mutations throughout the cytoplasmic end of S6 strongly influence hKv1.5 channel gating characteristics. Modification of hKv1.5 at positions T505, V512, and S515 resulted in large negative shifts in the voltage dependence of activation whereas modifications at position Y519 resulted in negative (Y519N) and positive (Y519F) shifts. When adjusted for the altered voltage sensitivity, activation kinetics of mutated channels were similar to WT; however, deactivation kinetics of mutations T505I, T505V, V512A, and V512M ({tau} = 35, 250, 170, and 420 ms, respectively) were still slower than WT ({tau} = 8.3 ms). In addition, deactivation of WT channels was highly temperature sensitive. However, deactivation of T505I and V512A channels was largely temperature insensitive. Taken together, these data suggest that mutations in S6 decouple activation from deactivation by altering the open state stability, and that residues on both sides of the highly conserved Pro-X-Pro sequence influence the movement of S6 during channel gating.




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