TRPM8 voltage sensor mutants reveal a mechanism for integrating thermal and chemical stimuli.

Article Details

Citation
Copy to clipboard

Voets T, Owsianik G, Janssens A, Talavera K, Nilius B

TRPM8 voltage sensor mutants reveal a mechanism for integrating thermal and chemical stimuli.

Nat Chem Biol. 2007 Mar;3(3):174-82. Epub 2007 Feb 11.

PubMed ID
17293875 [ View in PubMed
]
Abstract

TRPM8, a member of the transient receptor potential (TRP) channel superfamily, is expressed in thermosensitive neurons, in which it functions as a cold and menthol sensor. TRPM8 and most other temperature-sensitive TRP channels (thermoTRPs) are voltage gated; temperature and ligands regulate channel opening by shifting the voltage dependence of activation. The mechanisms and structures underlying gating of thermoTRPs are currently poorly understood. Here we show that charge-neutralizing mutations in transmembrane segment 4 (S4) and the S4-S5 linker of human TRPM8 reduce the channel's gating charge, which indicates that this region is part of the voltage sensor. Mutagenesis-induced changes in voltage sensitivity translated into altered thermal sensitivity, thereby establishing the strict coupling between voltage and temperature sensing. Specific mutations in this region also affected menthol affinity, which indicates a direct interaction between menthol and the TRPM8 voltage sensor. Based on these findings, we present a Monod-Wyman-Changeux-type model explaining the combined effects of voltage, temperature and menthol on TRPM8 gating.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
LevomentholTransient receptor potential cation channel subfamily M member 8IC 50 (nM)92000N/AN/ADetails
LevomentholTransient receptor potential cation channel subfamily M member 8Kd (nM)14400N/AN/ADetails
LevomentholTransient receptor potential cation channel subfamily M member 8EC 50 (nM)29000N/AN/ADetails