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Molecular and Cellular Biology, May 2005, p. 3630-3638, Vol. 25, No. 9
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.9.3630-3638.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The Phosphatidylinositol 3-Phosphate Phosphatase Myotubularin- Related Protein 6 (MTMR6) Is a Negative Regulator of the Ca²⁺-Activated K⁺ Channel K_Ca3.1

Department of Pharmacology, Skirball Institute of Biomolecular Medicine,¹ Department of Pediatrics, Division of Pediatric Cardiology,² Department of Physiology and Neurosciences, New York University School of Medicine, New York, New York 10016³

Received 27 August 2004/ Returned for modification 8 October 2004/ Accepted 31 January 2005

Myotubularins (MTMs) belong to a large subfamily of phosphatases that dephosphorylate the 3' position of phosphatidylinositol 3-phosphate [PI(3)P] and PI(3,5)P₂. MTM1 is mutated in X-linked myotubular myopathy, and MTMR2 and MTMR13 are mutated in Charcot-Marie-Tooth syndrome. However, little is known about the general mechanism(s) whereby MTMs are regulated or the specific biological processes regulated by the different MTMs. We identified a Ca²⁺-activated K channel, K_Ca3.1 (also known as KCa4, IKCa1, hIK1, or SK4), that specifically interacts with the MTMR6 subfamily of MTMs via coiled coil (CC) domains on both proteins. Overexpression of MTMR6 inhibited K_Ca3.1 channel activity, and this inhibition required MTMR6's CC and phosphatase domains. This inhibition is specific; MTM1, a closely related MTM, did not inhibit K_Ca3.1. However, a chimeric MTM1 in which the MTM1 CC domain was swapped for the MTMR6 CC domain inhibited K_Ca3.1, indicating that MTM CC domains are sufficient to confer target specificity. K_Ca3.1 was also inhibited by the PI(3) kinase inhibitors LY294002 and wortmannin, and this inhibition was rescued by the addition of PI(3)P, but not other phosphoinositides, to the patch pipette solution. PI(3)P also rescued the inhibition of K_Ca3.1 by MTMR6 overexpression. These data, when taken together, indicate that K_Ca3.1 is regulated by PI(3)P and that MTMR6 inhibits K_Ca3.1 by dephosphorylating the 3' position of PI(3)P, possibly leading to decreased PI(3)P in lipid microdomains adjacent to K_Ca3.1. K_Ca3.1 plays important roles in controlling proliferation by T cells, vascular smooth muscle cells, and some cancer cell lines. Thus, our findings not only provide unique insights into the regulation of K_Ca3.1 channel activity but also raise the possibility that MTMs play important roles in the negative regulation of T cells and in conditions associated with pathological cell proliferation, such as cancer and atherosclerosis.

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