Myotubularins (MTM) are a large subfamily of lipid phosphatases that 
specifically dephosphorylate at the D3 position of phosphatidylinositol 
3-phosphate (PI(3)P) in PI(3)P and PI(3,5)P2. We recently found that MTMR6 
specifically inhibits the Ca2+-activated K+ channel, KCa3.1, by 
dephosphorylating PI(3)P. We now show that inhibition is specific for MTMR6 and 
other MTMs do not inhibit KCa3.1. By replacing either or both of the coiled-coil 
(CC) and pleckstrin homology/GRAM (PH/G) domains of MTMs that failed to inhibit 
KCa3.1 with the CC and PH/G domains of MTMR6, we found that chimeric MTMs 
containing both the MTMR6 CC and PH/G domains functioned like MTMR6 to inhibit 
KCa3.1 channel activity, whereas chimeric MTMs containing either domain alone 
did not. Immunofluorescent microscopy demonstrated that both the MTMR6 CC and 
PH/G domains are required to co-localize MTMR6 to the plasma membrane with 
KCa3.1. These findings support a model in which two specific low affinity 
interactions are required to co-localize MTMR6 with KCa3.1: 1) between the CC 
domains on MTMR6 and KCa3.1 and (2) between the PH/G domain and a component of 
the plasma membrane. Our inability to detect significant interaction of the 
MTMR6 G/PH domain with phosphoinositides suggests that this domain may bind a 
protein. Identifying the specific binding partners of the CC and PH/G domains on 
other MTMs will provide important clues to the specific functions regulated by 
other MTMs as well as the mechanism(s) whereby loss of some MTMs lead to 
disease.