Document Detail

Surface expression and channel function of TRPM8 are cooperatively controlled by transmembrane segments S3 and S4.
MedLine Citation:
PMID:  23708837     Owner:  NLM     Status:  Publisher    
TRPM8 is a voltage-dependent cation channel additionally gated by cold temperatures, menthol, and icilin. Stimulation by the chemical agonists is at least in part mediated by a conserved sequence motif in transmembrane segment S3. Based on molecular dynamics simulation studies for TRPM8 a gating model was recently developed which predicts a direct electrostatic interaction between S3 and S4. Here, we performed charge reversal mutations to pinpoint possible interactions of the putative S4 voltage sensor with S3. The charge reversals R842D, R842E, and D835R in S4 prevented channel glycosylation and function, indicating a deficient insertion into the plasma membrane. The mutations R842D and R842E were specifically rescued by the reciprocal charge reversal D802R in S3. The alternative charge reversal in S3, D796R, failed to compensate for the dysfunction of the mutants R842D and R842E. Remarkably, the double charge reversal mutants R842D + D802R and R842E + D802R retained intrinsic voltage-sensitivity, although the critical voltage sensor arginine was substituted by a negatively charged residue. Likewise, the insertion of three additional positively charged residues into S4 did not crucially change the voltage-sensitivity of TRPM8 but abolished the sensitivity to icilin. We conclude that S4 does not play a separate role for the gating of TRPM8. Instead, the cooperation with the adjacent segment S3 and the combined charges in these two segments is of general importance for both channel maturation and channel function. This mechanism distinguishes TRPM8 from other voltage-dependent cation channels within and outside the TRP family.
Frank J P Kühn; Mathis Winking; Cornelia Kühn; Daniel C Hoffmann; Andreas Lückhoff
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-5-26
Journal Detail:
Title:  Pflugers Archiv : European journal of physiology     Volume:  -     ISSN:  1432-2013     ISO Abbreviation:  Pflugers Arch.     Publication Date:  2013 May 
Date Detail:
Created Date:  2013-5-27     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0154720     Medline TA:  Pflugers Arch     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Institute of Physiology, Medical Faculty, RWTH Aachen, D52057, Aachen, Germany,
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