The Phosphatidylinositol 3-Phosphate Phosphatase Myotubularin- Related Protein 6 (MTMR6) Is a Negative Regulator of the Ca2+-Activated K+ Channel KCa3.1

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Abstract
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, KCa3.1 (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 KCa3.1 channel activity, and this inhibition required MTMR69s CC and phosphatase domains. This inhibition is specific; MTM1, a closely related MTM, did not inhibit KCa3.1. However, a chimeric MTM1 in which the MTM1 CC domain was swapped for the MTMR6 CC domain inhibited KCa3.1, indicating that MTM CC domains are sufficient to confer target specificity. KCa3.1 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 KCa3.1 by MTMR6 overexpression. These data, when taken together, indicate that KCa3.1 is regulated by PI(3)P and that MTMR6 inhibits KCa3.1 by dephosphorylating the 3′ position of PI(3)P, possibly leading to decreased PI(3)P in lipid microdomains adjacent to KCa3.1. KCa3.1 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 KCa3.1 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.