Sci. STKE, 27 February 2007
Channels Dueling Regulators
Elizabeth M. Adler
Science's STKE, AAAS, Washington, DC 20005, USA
To investigate the mechanisms whereby phosphoinositides (PIs) regulate members of the TRP (transient receptor potential) family of ion channels, Kwon et al. focused on TRPC6, a channel modulated both by phosphatidylinositol 3,4,5-trisphosphate (PIP3) and by calmodulin. Various PIs bound directly to a fusion protein containing the C-terminal region of TRPC6, and mutational analysis revealed that the PI-binding site overlapped that for calmodulin (PCaM domain). PIs disrupted calmodulin binding to the C-terminal region of TRPC6 in an in vitro assay, with PIP3 being most potent; mutational analysis indicated that this interaction involved the PCaM domain. When expressed in human embryonic kidney (HEK) 293T cells, a TRPC6 mutant associated with decreased potency of PIs in disrupting calmodulin binding displayed reduced whole-cell currents relative to wild-type after TRPC6 activation, whereas a TRPC6 mutant associated with enhanced potency of PI disruption of calmodulin binding showed larger peak currents. Experiments in which intracellular calcium was buffered or in which calmodulin was overexpressed supported the idea that calcium-calmodulin inhibits TRPC6 activity and that PIs enhance TRPC6 function by disrupting the TRPC6-calmodulin interaction, as did experiments in which an AKT-PH domain was overexpressed to act as a PIP3 "sponge." Other TRP family channels thought to bind calmodulin also bound PIs; with some of these, PIs reduced calmodulin binding. PIs also reduced calmodulin binding to the KCNQ1 potassium channel and the Cav1.2 calcium channel. Thus, the authors propose that PI regulation of calmodulin binding may represent a common mechanism for modulating ion channel function.
Y. Kwon, T. Hofmann, C. Montell, Integration of phosphoinositide- and calmodulin-mediated regulation of TRPC6. Mol. Cell 25, 491-503 (2007). [Online Journal]
Citation: E. M. Adler, Dueling Regulators. Sci. STKE 2007, tw68 (2007).
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