Section of Cell Signaling, Okazaki Institute for Integrative Bioscience, National Institutes of Natural Sciences, Okazaki 444-8787, Japan.
J Neurosci. 2013 Apr 3;33(14):6154-9. doi: 10.1523/JNEUROSCI.5672-12.2013.
Cold sensation is an important and fundamental sense for animals and it is known to be affected by ambient temperature. Transient Receptor Potential Melastatin 8 (TRPM8), a nonselective cation channel expressed in a subset of peripheral afferent fibers, acts as a cold sensor, having an activation threshold of ∼28°C. Although the cold temperature threshold of TRPM8 is affected by menthol or pH, ambient temperature has not been reported to affect it. Because the cold temperature threshold was thought to be unchanged by alterations in ambient temperature, the relativity of temperature sensing in different ambient temperatures could not be understood at the level of molecular function of thermosensitive TRP channels. Here, we show that ambient temperature changed the temperature threshold for activation of human and rat TRPM8 in a heterologous expression system and cold responses in mouse DRG neurons. Moreover, reducing the level of cellular phosphatidylinositol 4,5-bisphosphate (PIP2) attenuated changes in the cold temperature threshold after alterations in ambient temperature. A single amino acid mutation at position 1008 in the C terminus of TRPM8 (arginine to glutamine) also attenuated changes in the cold temperature threshold induced by ambient temperature. These findings suggest that ambient temperature does affect the temperature threshold for TRPM8 activation through interaction of PIP2.
冷觉是动物的一种重要基本感觉，已知其受环境温度的影响。瞬时受体电位阳离子通道亚家族 M 成员 8（TRPM8）是一种在外周传入纤维的亚群中表达的非选择性阳离子通道，作为冷感受器，其激活阈值约为 28°C。尽管 TRPM8 的冷温度阈值受薄荷醇或 pH 值的影响，但环境温度尚未被报道会影响它。由于冷温度阈值被认为不受环境温度变化的影响，因此在不同环境温度下温度感应的相关性在热敏性 TRP 通道的分子功能水平上无法理解。在这里，我们表明，环境温度改变了人源和鼠源 TRPM8 在异源表达系统中的激活温度阈值，以及小鼠背根神经节神经元的冷反应。此外，降低细胞内磷脂酰肌醇 4,5-二磷酸（PIP2）的水平可减弱环境温度变化后冷温度阈值的变化。TRPM8 羧基末端第 1008 位单个氨基酸突变（精氨酸突变为谷氨酰胺）也可减弱环境温度引起的冷温度阈值变化。这些发现表明，环境温度确实通过 PIP2 的相互作用影响 TRPM8 激活的温度阈值。
