Regulation of the Ca2+ Sensitivity of the Nonselective Cation Channel TRPM4

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 muta...

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Bibliographic Details
Published in:The Journal of biological chemistry 2005-02, Vol.280 (8), p.6423-6433
Main Authors: Nilius, Bernd, Prenen, Jean, Tang, Jisen, Wang, Chunbo, Owsianik, Grzegorz, Janssens, Annelies, Voets, Thomas, Zhu, Michael X.
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - pharmacology
Binding Sites
Calcium - pharmacology
Calcium Channels - genetics
Calcium Channels - metabolism
Calcium Channels - physiology
Calmodulin - metabolism
Cation Transport Proteins - genetics
Cation Transport Proteins - metabolism
Cation Transport Proteins - physiology
Cell Line
Electrophysiology
Humans
Mutation
Phosphorylation
Protein Kinase C - metabolism
TRPM Cation Channels
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Summary: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 Ca2+ 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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M411089200