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Articles in PresS, published online ahead of print December 7, 2001
Am J Physiol Renal Physiol, 10.1152/ajprenal.00300.2001
Submitted on September 25, 2001
Accepted on November 26, 2001
1 Internal Medicine, UT Southwestern Medical Center at Dallas, Dallas, Texas, USA
2 Biochemistry, UT Southwestern Medical Center at Dallas, Dallas, Texas, USA
* To whom correspondence should be addressed. E-mail: Chou-long.Huang{at}UTSouthwestern.edu.
We have recently reported that direct interaction between phosphatidylinositol-4,5-bisphosphate (PIP2) and the C-terminal cytoplasmic domain of ROMK1 is important for opening of the channel. We identified arginine -188 of ROMK1 as a critical residue for this interaction. Here, we further report that substitution of a neutral amino acid for lysine-181, arginine-217 or lysine-218 decreases single-channel open probability for the full-conductance state and increases the frequency of opening at a sub-conductance state. Compared to wild type ROMK1 channels, these substitution mutants also display an increased sensitivity to the block by anti-PIP2 antibodies and to inhibition by intracellular protons. These results indicate that, like arginine-188, lysine-181, arginine-217, and lysine-218 are also involved in interaction with PIP2 and are critical for ROMK1 to open at full-conductance. Using synthetic phosphoinositides containing phosphates at different positions in the head group, we also examined the specificities of phosphoinositides in the regulation of ROMK1 channels. We found that phosphoinositides containing phosphate at both 4 and 5 positions of the inositol head group have the highest efficacy in activating ROMK1 channels. These results suggest that phosphatidylinositol-4,5-bisphosphate is likely the important phosphoinositide in the regulation of ROMK1 channel in a physiological membrane milieu.
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