TRPM4, a Ca2+-activated cation channel of the transient receptor potential superfamily, undergoes a fast desensitization to Ca2+. The mechanisms underlying the alterations in Ca2+ sensitivity are unknown. Here we show that cytoplasmic ATP reversed Ca2+ sensitivity after desensitization, whereas mutations to putative ATP binding sites resulted in faster and more complete desensitization. Phorbol ester-induced activation of protein kinase C (PKC) increased the Ca2+ sensitivity of wild-type TRPM4 but not of two mutants mutated at putative PKC phosphorylation sites. Overexpression of a calmodulin mutant unable to bind Ca2+ dramatically reduced TRPM4 activation. We identified five Ca2+- calmodulin binding sites in TRPM4 and showed that deletion of any of the three C-terminal sites strongly impaired current activation by reducing Ca 2+ sensitivity and shifting the voltage dependence of activation to very positive potentials. Thus, the Ca2+ sensitivity of TRPM4 is regulated by ATP, PKC-dependent phosphorylation, and calmodulin binding at the C terminus. © 2005 by The American Society for Biochemistry and Molecular Biology, Inc.
CITATION STYLE
Nilius, B., Prenen, J., Tang, J., Wang, C., Owsianik, G., Janssens, A., … Zhu, M. X. (2005). Regulation of the Ca2+ sensitivity of the nonselective cation channel TRPM4. Journal of Biological Chemistry, 280(8), 6423–6433. https://doi.org/10.1074/jbc.M411089200
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