Key result
Calml3 renders KCNQ1 channels resistant to PIP2 depletion as an alternative to calmodulin.
Calml3 can serve as an alternative to calmodulin in assembling with KCNQ1 channels, highlighting the molecular diversity of endogenous epithelial KCNQ1 channels.
BACKGROUND/AIMS: KCNQ channels transport K+ ions and participate in various cellular functions. The channels directly assemble with auxiliary proteins such as a ubiquitous Ca2+- sensor protein, calmodulin (CaM), to configure the physiological properties in a tissue-specific manner. Although many CaM-like Ca2+-sensor proteins have been identified in eukaryotes, how KCNQ channels selectively interact with CaM and how the homologues modulate the functionality of the channels remain unclear. METHODS: We developed protocols to evaluate the interaction between the green fluorescent protein-tagged C-terminus of KCNQ1 (KCNQ1cL) and Ca2+-sensors by detecting its fluorescence in size exclusion chromatography and electrophoresed gels. The effects of Ca2+-sensor proteins on KCNQ1 activity was measured by two electrode voltage clamp technique of Xenopus oocytes. RESULTS: When co-expressed CaM and KCNQ1cL, they assemble in a 4:4 stoichiometry, forming a hetero-octamer. Among nine CaM homologues tested, Calml3 was found to form a hetero-octamer with KCNQ1cL and to associate with the full-length KCNQ1 in a competitive manner with CaM. When co-expressed in oocytes, Calml3 rendered KCNQ1 channels resistant to the voltage-dependent depletion of phosphatidylinositol 4,5-bisphosphate by voltage-sensitive phosphatase. CONCLUSION: Since Calml3 is closely related to CaM and is prominently expressed in epithelial cells, Calml3 may be a constituent of epithelial KCNQ1 channels and underscores the molecular diversity of endogenous KCNQ1 channels.
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Inanobe et al. (2015) studied this question. Calml3 co-expression vs. CaM or KCNQ1 alone was evaluated on Interaction and functional modulation of KCNQ1 channels. Calml3 forms a hetero-octamer with KCNQ1 and renders the channels resistant to voltage-dependent depletion of PIP2, acting as an alternative to calmodulin in epithelial cells.
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