Downregulation of transient receptor potential melastatin 8 by protein kinase C-mediated dephosphorylation
Downregulation of transient receptor potential melastatin 8 by protein kinase C-mediated dephosphorylation
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DOI：
10.1523/jneurosci.3006-05.2005
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发表时间：
2005-12-07
影响因子：
5.3
通讯作者：
Pimentel, F
中科院分区：
文献类型：
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作者：
Premkumar, LS;Raisinghani, M;Pimentel, F
瞬时受体电位 melastatin 8 (TRPM8) 和瞬时受体电位 vanilloid 1 (TRPV1) 分别是检测冷感和热感的离子通道。它们的激活使周围神经末梢去极化，导致动作电位通过脊髓传播到大脑。这些受体还在背根神经节（DRG）和背角（DH）神经元之间的突触传递中发挥重要作用。在这里，我们表明，与克隆和天然受体中TRPV1的上调相比，TRPM8通过蛋白激酶C（PKC）的激活而在功能上下调，导致膜电流的抑制和细胞内Ca2+的增加。缓激肽通过激活 DRG 神经元中的 PKC 显着下调 TRPM8。在 DRG 和 DH 神经元之间的第一个感觉突触处激活 TRPM8 或 TRPV1 会导致自发/微型 EPSC 的频率大幅增加。 PKC 激活会减弱 TRPM8 并促进 TRPV1 介导的突触传递。值得注意的是，下调可归因于 PKC 介导的 TRPM8 去磷酸化，而磷酸酶抑制剂可以逆转这种去磷酸化。这些发现表明TRPV1介导的炎症性热痛觉过敏可能会因TRPM8的下调而进一步加剧，因为后者可以介导急需的清凉/舒缓感觉。
Transient receptor potential melastatin 8 (TRPM8) and transient receptor potential vanilloid 1 (TRPV1) are ion channels that detect cold and hot sensations, respectively. Their activation depolarizes the peripheral nerve terminals resulting in action potentials that propagate to brain via the spinal cord. These receptors also play a significant role in synaptic transmission between dorsal root ganglion (DRG) and dorsal horn (DH) neurons. Here, we show that TRPM8 is functionally downregulated by activation of protein kinase C (PKC) resulting in inhibition of membrane currents and increases in intracellular Ca2+ compared with upregulation of TRPV1 in cloned and native receptors. Bradykinin significantly downregulates TRPM8 via activation of PKC in DRG neurons. Activation of TRPM8 or TRPV1 at first sensory synapse between DRG and DH neurons leads to a robust increase in frequency of spontaneous/miniature EPSCs. PKC activation blunts TRPM8- and facilitates TRPV1-mediated synaptic transmission. Significantly, downregulation is attributable to PKC-mediated dephosphorylation of TRPM8 that could be reversed by phosphatase inhibitors. These findings suggest that inflammatory thermal hyperalgesia mediated by TRPV1 may be further aggravated by downregulation of TRPM8, because the latter could mediate the much needed cool/soothing sensation.