title: The membrane-associated transient receptor potential vanilloid channel is the central heat shock receptor controlling the cellular heat shock response in epithelial cells.
abstract: The heat shock response (HSR) is a highly conserved molecular response to various types of stresses, including heat shock, during which heat-shock proteins (Hsps) are produced to prevent and repair damages in labile proteins and membranes. In cells, protein unfolding in the cytoplasm is thought to directly enable the activation of the heat shock factor 1 (HSF-1), however, recent work supports the activation of the HSR via an increase in the fluidity of specific membrane domains, leading to activation of heat-shock genes. Our findings support the existence of a plasma membrane-dependent mechanism of HSF-1 activation in animal cells, which is initiated by a membrane-associated transient receptor potential vanilloid receptor (TRPV). We found in various non-cancerous and cancerous mammalian epithelial cells that the TRPV1 agonists, capsaicin and resiniferatoxin (RTX), upregulated the accumulation of Hsp70, Hsp90 and Hsp27 and Hsp70 and Hsp90 respectively, while the TRPV1 antagonists, capsazepine and AMG-9810, attenuated the accumulation of Hsp70, Hsp90 and Hsp27 and Hsp70, Hsp90, respectively. Capsaicin was also shown to activate HSF-1. These findings suggest that heat-sensing and signaling in mammalian cells is dependent on TRPV channels in the plasma membrane. Thus, TRPV channels may be important drug targets to inhibit or restore the cellular stress response in diseases with defective cellular proteins, such as cancer, inflammation and aging.
authors.affiliation: Dept. of Anesthesiology and Critical Care Medicine and the Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University School of Medicine, Jerusalem, Israel.
authors.forename: Zohar
authors.initials: Z
authors.lastname: Bromberg
authors.forename: Pierre
authors.initials: P
authors.lastname: Goloubinoff
authors.forename: Younousse
authors.initials: Y
authors.lastname: Saidi
authors.forename: Yoram George
authors.initials: YG
authors.lastname: Weiss
mesh_terms: D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D018869:Heat-Shock Response / Q000187:drug effects / Q000235:genetics; D006801:Humans; D011485:Protein Binding; D021381:Protein Transport / Q000187:drug effects; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D014157:Transcription Factors; C071423:capsazepine; D002211:Capsaicin