Conserved gating elements in TRPC4 and TRPC5 channels

• Published in: Journal of Biological Chemistry
• Main Author: Beck A.; Speicher T.; Stoerger C.; Sell T.; Dettmer V.; Jusoh S.A.; Abdulmughni A.; Cavalié A.; Philipp S.E.; Zhu M.X.; Helms V.; Wissenbach U.; Flockerzi V.
• Format: Article
• Language: English
• Published: 2013
• Online Access: https://www.scopus.com/inward/record.uri?eid=2-s2.0-84880072077&doi=10.1074%2fjbc.M113.478305&partnerID=40&md5=b8fe7638c740d78199aa4a03e1cd0988

TRPC4 and TRPC5 proteins share 65% amino acid sequence identity and form Ca2+-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 Ca2+ 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. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc.