The Transient Receptor Potential Channel TRPM8 Is Inhibited via the α2A Adrenoreceptor Signaling Pathway
The Transient Receptor Potential Channel TRPM8 Is Inhibited via the α2A Adrenoreceptor Signaling Pathway
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DOI：
10.1074/jbc.m109.069377
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发表时间：
2010-03-26
影响因子：
4.8
通讯作者：
Prevarskaya, Natalia
中科院分区：
文献类型：
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作者：
Bavencoffe, Alexis;Gkika, Dimitra;Prevarskaya, Natalia
瞬时受体电位通道melastatin成员8（TRPM 8）在感觉神经元中表达，在那里它构成了环境无害寒冷（10-25摄氏度）的主要受体。在感觉神经元中表达的几种类型的G蛋白偶联受体中，已知G（i）偶联α 2A-肾上腺素受体（α 2A-AR）参与体温调节;然而，其潜在的分子机制仍然知之甚少。在这里，我们证明了刺激α 2A-AR抑制TRPM 8在感觉神经元从大鼠背根神经节（DRG）。此外，使用特定的药理学和分子工具结合膜片钳电流记录，我们发现在异源表达的HEK-293（人胚肾）细胞中，TRPM 8通道受到G（i）蛋白/腺苷酸环化酶（AC）/cAMP/蛋白激酶A（PKA）信号级联的抑制。我们进一步鉴定了TRPM 8 S9和T17作为调节TRPM 8通道活性的两个关键PKA磷酸化位点。因此，我们提出通过α 2A-AR信号级联抑制TRPM 8可能构成生理和病理条件下温度感觉调节的新机制。
The transient receptor potential channel melastatin member 8 (TRPM8) is expressed in sensory neurons, where it constitutes the main receptor of environmental innocuous cold (10-25 degrees C). Among several types of G protein-coupled receptors expressed in sensory neurons, G(i)-coupled alpha 2A-adrenoreceptor (alpha 2A-AR), is known to be involved in thermoregulation; however, the underlying molecular mechanisms remain poorly understood. Here we demonstrated that stimulation of alpha 2A-AR inhibited TRPM8 in sensory neurons from rat dorsal root ganglia (DRG). In addition, using specific pharmacological and molecular tools combined with patch-clamp current recordings, we found that in heterologously expressed HEK-293 (human embryonic kidney) cells, TRPM8 channel is inhibited by the G(i) protein/adenylate cyclase (AC)/cAMP/protein kinase A (PKA) signaling cascade. We further identified the TRPM8 S9 and T17 as two key PKA phosphorylation sites regulating TRPM8 channel activity. We therefore propose that inhibition of TRPM8 through the alpha 2A-AR signaling cascade could constitute a new mechanism of modulation of thermosensation in both physiological and pathological conditions.