Role of FK506 binding protein 12 in morphine-induced μ-opioid receptor internalization and desensitization.
Role of FK506 binding protein 12 in morphine-induced μ-opioid receptor internalization and desensitization.
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FK506 结合蛋白 12 在吗啡诱导的 μ-阿片受体内化和脱敏中的作用
DOI：
10.1016/j.neulet.2014.02.059
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发表时间：
2014-04-30
影响因子：
2.5
通讯作者：
Qiu Y
中科院分区：
文献类型：
--
作者：
Yan YH;Wang Y;Zhao LX;Jiang S;Loh HH;Law PY;Chen HZ;Qiu Y
激动剂激活的μ-阿片受体(OPRM1)通过G蛋白偶联受体激酶和随后的β-arrestin募集而经历强大的受体磷酸化，触发受体内化和脱敏。吗啡是一种被广泛使用的阿片类药物，它能低效地诱导受体磷酸化。以前我们报道了FK506结合蛋白12(FKBP12)与OPRM1特异性地相互作用，这种相互作用减弱了受体的磷酸化，促进了吗啡诱导的蛋白激酶C的募集和激活。在本研究中，我们证明了FKBP12与OPRM1的关联也影响了吗啡诱导的受体内化和G蛋白依赖的腺酰环化酶脱敏。在表达OPRM1的细胞中，当Pro353突变为不与FKBP12相互作用的ALA(OPRM1P353A)时，或在解离受体-FKBP12相互作用的FK506的存在下，吗啡诱导更快的受体内化和腺苷环化酶脱敏。此外，siRNA下调细胞FKBP12水平可加速吗啡诱导的受体内化和腺苷环化酶脱敏。我们的研究进一步证明FKBP12的肽基-脯氨基顺反异构酶活性可能在抑制受体磷酸化中起作用。内化受体循环，从而抵消镇痛耐受的发展，认为受体与FKBP12的关联也可能通过调节受体运输而促进吗啡耐受的发展。
Agonist-activated μ-opioid receptor (OPRM1) undergoes robust receptor phosphorylation by G protein-coupled receptor kinases and subsequent β-arrestin recruitment, triggering receptor internalization and desensitization. Morphine, a widely prescribed opioid, induces receptor phosphorylation inefficiently. Previously we reported that FK506 binding protein 12 (FKBP12) specifically interacts with OPRM1 and such interaction attenuates receptor phosphorylation and facilitates morphine-induced recruitment and activation of protein kinase C. In the current study, we demonstrated that the association of FKBP12 with OPRM1 also affects morphine-induced receptor internalization and G protein-dependent adenylyl cyclase desensitization. Morphine induced faster receptor internalization and adenylyl cyclase desensitization in cells expressing OPRM1 with Pro353mutated to Ala (OPRM1P353A), which does not interact with FKBP12, or in the presence of FK506 which dissociates the receptor-FKBP12 interaction. Furthermore, knockdown of cellular FKBP12 level by siRNA accelerated morphine-induced receptor internalization and adenylyl cyclase desensitization. Our study further demonstrated that peptidyl prolyl cis-trans isomerase activity of FKBP12 probably plays a role in inhibition of receptor phosphorylation. In the view that internalized receptor recycles and thus counteracts the development of analgesic tolerance, receptor’s association with FKBP12 could also contribute to the development of morphine tolerance through modulation of receptor trafficking.
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影响因子：
4.8
作者：
Chu J;Zheng H;Zhang Y;Loh HH;Law PY
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