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.
Highlights
Mechanistic understanding of complex regulation of sensory transient receptor potential (TRP) channels can be facilitated by quantitative single-channel analysis
We used single-channel analysis to explore the kinetic mechanisms underlying the modulation of TRPM8 channels by short TRPM8 isoforms and several chemical compounds
Voets et al [28] showed previously that mutations in S4 reduce the gating charge of TRPM8 and alter the thermosensitivity, suggesting that voltage sensors may be associated with S4 and that there is coupling between voltage and temperature activation
Summary
Mechanistic understanding of complex regulation of sensory transient receptor potential (TRP) channels can be facilitated by quantitative single-channel analysis. The TRPM8 channel has been extensively investigated as the major neuronal cold sensor, it is 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 investigate TRPM8 inhibition in cell-attached patches using HEK293 cells expressing TRPM8 alone or coexpressed with its short sM8-6 isoform. We 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. Inhibition by BCTC and that by clotrimazole share a different set of common features
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