A-kinase anchoring protein 150 controls protein kinase C-mediated phosphorylation and sensitization of TRPV1.
A-kinase anchoring protein 150 controls protein kinase C-mediated phosphorylation and sensitization of TRPV1.
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DOI：
10.1016/j.pain.2009.08.002
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发表时间：
2009-12
期刊：
影响因子：
7.4
通讯作者：
Henry MA
中科院分区：
文献类型：
--
作者：
Jeske NA;Patwardhan AM;Ruparel NB;Akopian AN;Shapiro MS;Henry MA
各种受体蛋白的翻译后修饰对受体活化具有显著影响。对于瞬时受体电位家族V 1型（TRPV 1）受体，某些丝氨酸/苏氨酸氨基酸残基的磷酸化使受体对辣椒素和热的活化敏感。虽然蛋白激酶C（PKC）磷酸化TRPV 1的某些丝氨酸/苏氨酸残基，它是不完全了解如何PKC功能与TRPV 1。最近的研究报道，在一些伤害性模型中，A-激酶调节蛋白150（AKAP 150）介导TRPV 1的PKA磷酸化。在这里，我们证明了AKAP 150也介导了PKC介导的TRPV 1磷酸化和致敏。在培养的大鼠三叉神经节中，免疫细胞化学分析显示AKAP 150和PKC亚型α、δ、ε和γ在TRPV 1阳性神经元中共定位。其他生化证据支持免疫细胞化学结果，表明AKAP 150优先与某些PKC亚型在大鼠三叉神经节神经元。利用siRNA介导的AKAP 150表达的敲低，我们证明了PKC介导的TRPV 1磷酸化和对辣椒素反应的敏化依赖于AKAP 150支架蛋白的功能表达。此外，相对于野生型，PKC诱导的对热刺激的敏感性在AKAP 150敲除动物中被消除。总的来说，这些研究的结果表明，AKAP 150支架蛋白功能调节PKC介导的磷酸化和敏化的TRPV 1受体在大鼠感觉神经元，这表明支架蛋白是外周炎性痛觉过敏的一个不可或缺的调节器。
Post-translational modifications on various receptor proteins have significant effects on receptor activation. For the Transient Receptor Potential family V type 1 (TRPV1) receptor, phosphorylation of certain serine/threonine amino acid residues sensitizes the receptor to activation by capsaicin and heat. Although Protein Kinase C (PKC) phosphorylates TRPV1 on certain serine/threonine residues, it is not completely understood how PKC functionally associates with TRPV1. Recent studies have reported that the A-kinase Anchoring Protein 150 (AKAP150) mediates PKA phosphorylation of TRPV1 in several nociceptive models. Here, we demonstrate that AKAP150 also mediates PKC-directed phosphorylation and sensitization of TRPV1. In cultured rat trigeminal ganglia, immunocytochemical analyses demonstrate co-localization of AKAP150 and PKC isoforms α, δ, ε, and γ in TRPV1-positive neurons. Additional biochemical evidence supports immunocytochemical results, indicating that AKAP150 preferentially associates with certain PKC isoforms in rat trigeminal ganglia neurons. Employing siRNA-mediated knock-down of AKAP150 expression, we demonstrate that PKC-mediated phosphorylation of TRPV1 and sensitization to a capsaicin response is dependent upon functional expression of the AKAP150 scaffolding protein. Furthermore, PKC-induced sensitization to a thermal stimulus is abrogated in AKAP150 knock-out animals relative to wild-type. Collectively, results from these studies indicate that the AKAP150 scaffolding protein functionally modulates PKC-mediated phosphorylation and sensitization of the TRPV1 receptor in rat sensory neurons, suggesting the scaffolding protein to be an integral regulator of peripheral inflammatory hyperalgesia.
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