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Vol. 17, Issue 1, 146-154, January 2006

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Phosphatidylinositol 3-Phosphate Indirectly Activates KCa3.1 via 14 Amino Acids in the Carboxy Terminus of KCa3.1

Shekhar Srivastava ^* , Papiya Choudhury ^* , Zhai Li ^*, GongXin Liu , Vivek Nadkarni , Kyung Ko ^*, William A. Coetzee ^* , and Edward Y. Skolnik ^* 

^* Department of Pharmacology, The Skirball Institute, New York University School of Medicine, New York, NY 10016; Departments of Pediatric Cardiology, The Skirball Institute, New York University School of Medicine, New York, NY 10016; and Departments of Division of Nephrology, The Skirball Institute, New York University School of Medicine, New York, NY 10016

Submitted August 15, 2005; Revised September 20, 2005; Accepted October 14, 2005
Monitoring Editor: Guido Guidotti

KCa3.1 is an intermediate conductance Ca²⁺-activated K⁺ channel that is expressed predominantly in hematopoietic cells, smooth muscle cells, and epithelia where it functions to regulate membrane potential, Ca²⁺ influx, cell volume, and chloride secretion. We recently found that the KCa3.1 channel also specifically requires phosphatidylinositol-3 phosphate [PI(3)P] for channel activity and is inhibited by myotubularin-related protein 6 (MTMR6), a PI(3)P phosphatase. We now show that PI(3)P indirectly activates KCa3.1. Unlike KCa3.1 channels, the related KCa2.1, KCa2.2, or KCa2.3 channels do not require PI(3)P for activity, suggesting that the KCa3.1 channel has evolved a unique means of regulation that is critical for its biological function. By making chimeric channels between KCa3.1 and KCa2.3, we identified a stretch of 14 amino acids in the carboxy-terminal calmodulin binding domain of KCa3.1 that is sufficient to confer regulation of KCa2.3 by PI(3)P. However, mutation of a single potential phosphorylation site in these 14 amino acids did not affect channel activity. These data together suggest that PI(3)P and these 14 amino acids regulate KCa3.1 channel activity by recruiting an as yet to be defined regulatory subunit that is required for Ca²⁺ gating of KCa3.1.

These authors contributed equally to this work.

Address correspondence to: Edward Skolnik (skolnik{at}saturn.med.nyu.edu).

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