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首页> 外文期刊>Journal of cellular physiology. >Regulation of TRPM8 channel activity by Src-mediated tyrosine phosphorylation
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Regulation of TRPM8 channel activity by Src-mediated tyrosine phosphorylation

机译：TRPM8渠道活动的监管Src-mediated酪氨酸磷酸化

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摘要

The transient receptor potential melastatin type 8 (TRPM8) receptor channel is expressed in primary afferent neurons where it is the main transducer of innocuous cold temperatures and also in a variety of tumors, where it is involved in progression and metastasis. Modulation of this channel by intracellular signaling pathways has therefore important clinical implications. We investigated the modulation of recombinant and natively expressed TRPM8 by the Src kinase, which is known to be involved in cancer pathophysiology and inflammation. Human TRPM8 expressed in HEK293T cells is constitutively tyrosine phosphorylated by Src which is expressed either heterologously or endogenously. Src action on TRPM8 potentiates its activity, as treatment with PP2, a selective Src kinase inhibitor, reduces both TRPM8 tyrosine phosphorylation and cold-induced channel activation. RNA interference directed against the Src kinase diminished the extent of PP2-induced functional down-regulation of TRPM8, confirming that PP2 acts mainly through Src inhibition. Finally, the effect of PP2 on TRPM8 cold activation was reproduced in cultured rat dorsal root ganglion neurons, and this action was antagonized by the protein tyrosine phosphatase inhibitor pervanadate, confirming that TRPM8 activity is sensitive to the cellular balance between tyrosine kinases and phosphatases. This positive modulation of TRPM8 by Src kinase may be relevant for inflammatory pain and cancer signaling.
机译：瞬时受体电位melastatin类型8(TRPM8)受体表达的主要频道传入神经元的主要传感器无害的低温和也各种肿瘤,参与进展和转移。通道由胞内信号通路因此重要的临床意义。重组的调制和调查本机由Src TRPM8激酶表达,是参与癌症病理生理学和炎症。由酪氨酸观察HEK293T细胞磷酸化的Src表示从内部不同的或。TRPM8强化其活动,如治疗PP2,选择性Src激酶抑制剂,减少TRPM8酪氨酸磷酸化和诱使通道激活。针对Src激酶减弱程度PP2-induced功能下调主要通过TRPM8,确认PP2行为Src抑制。TRPM8冷激活在培养复制大鼠背根神经节神经元,这行动由蛋白质酪氨酸与磷酸酶抑制剂pervanadate,确认TRPM8活动是敏感的细胞酪氨酸激酶和之间的平衡磷酸酶。由Src激酶可能与炎症相关疼痛和癌症信号。

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