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Conserved gating elements in TRPC4 and TRPC5 channels.

Beck, Andreas; Speicher, Tilman; Stoerger, Christof; Sell, Thomas; Dettmer, Viviane; Jusoh, Siti A; Abdulmughni, Ammar; Cavalié, Adolfo; Philipp, Stephan E; Zhu, Michael X; Helms, Volkhard; Wissenbach, Ulrich; Flockerzi, Veit.
J Biol Chem; 288(27): 19471-83, 2013 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-23677990
TRPC4 and TRPC5 proteins share 65% amino acid sequence identity and form Ca(2+)-permeable nonselective cation channels. They are activated by stimulation of receptors coupled to the phosphoinositide signaling cascade. Replacing a conserved glycine residue within the cytosolic S4-S5 linker of both proteins by a serine residue forces the channels into an open conformation. Expression of the TRPC4G503S and TRPC5G504S mutants causes cell death, which could be prevented by buffering the Ca(2+) of the culture medium. Current-voltage relationships of the TRPC4G503S and TRPC5G504S mutant ion channels resemble that of fully activated TRPC4 and TRPC5 wild-type channels, respectively. Modeling the structure of the transmembrane domains and the pore region (S4-S6) of TRPC4 predicts a conserved serine residue within the C-terminal sequence of the predicted S6 helix as a potential interaction site. Introduction of a second mutation (S623A) into TRPC4G503S suppressed the constitutive activation and partially rescued its function. These results indicate that the S4-S5 linker is a critical constituent of TRPC4/C5 channel gating and that disturbance of its sequence allows channel opening independent of any sensor domain.
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