title: Short isoforms of the cold receptor TRPM8 inhibit channel gating by mimicking heat action rather than chemical inhibitors.
abstract: Transient receptor potential (TRP) channels couple various environmental factors to changes in membrane potential, calcium influx, and cell signaling. They also integrate multiple stimuli through their typically polymodal activation. Thus, although the TRPM8 channel has been extensively investigated as the major neuronal cold sensor, it is also regulated by various chemicals, as well as by several short channel isoforms. Mechanistic understanding of such complex regulation is facilitated by quantitative single-channel analysis. We have recently proposed a single-channel mechanism of TRPM8 regulation by voltage and temperature. Using this gating mechanism, we now investigate TRPM8 inhibition in cell-attached patches using HEK293 cells expressing TRPM8 alone or coexpressed with its short sM8-6 isoform. This is compared with inhibition by the chemicals N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)piperazine-1-carboxamide (BCTC) and clotrimazole or by elevated temperature. We found that within the seven-state single-channel gating mechanism, inhibition of TRPM8 by short sM8-6 isoforms closely resembles inhibition by increased temperature. In contrast, inhibition by BCTC and that by clotrimazole share a different set of common features.
authors: Center for Vision and Vascular Science, Queen's University Belfast, BT12 6BA Belfast, United Kingdom. jfernandezgonzalez01@qub.ac.uk
authors: José A
authors: JA
authors: Fernández
authors: Roman
authors: R
authors: Skryma
authors: Gabriel
authors: G
authors: Bidaux
authors: Karl L
authors: KL
authors: Magleby
authors: C Norman
authors: CN
authors: Scholfield
authors: J Graham
authors: JG
authors: McGeown
authors: Natalia
authors: N
authors: Prevarskaya
authors: Alexander V
authors: AV
authors: Zholos
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology*; D003022:Clotrimazole / Q000494:pharmacology*; D057809:HEK293 Cells; D006358:Hot Temperature; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects* / Q000502:physiology*; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D013823:Thermoreceptors / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; C475772:N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2H)-carboxamide; D020033:Protein Isoforms; D011719:Pyrazines; D011725:Pyridines; D050053:TRPM Cation Channels; C425966:TRPM8 protein, human; D003022:Clotrimazole