Src promotes delta opioid receptor (DOR) desensitization by interfering with receptor recycling.
Src promotes delta opioid receptor (DOR) desensitization by interfering with receptor recycling.
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DOI：
10.1111/j.1582-4934.2008.00308.x
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发表时间：
2009-01
影响因子：
5.3
通讯作者：
Pineyro G
中科院分区：
文献类型：
--
作者：
Archer-Lahlou E;Audet N;Amraei MG;Huard K;Paquin-Gobeil M;Pineyro G
阿片类药物临床使用的一个重要限制是随着时间的推移，镇痛效果逐渐丧失。镇痛耐受的发展与受体脱敏密切相关。在δ阿片受体（DOR）的情况下，脱敏特别迅速，因为受体迅速内化，并且很难再循环到膜。在本研究中，我们调查是否Src活动有助于这种排序模式和功能脱敏的DORs。第一系列的实验表明，激动剂结合激活Src和不稳定的组成型复合物形成的自发协会的DORs与激酶。然后通过显示用Src抑制剂PP 2（20 μM; 1小时）预处理或转染显性失活Src突变体在持续暴露于激动剂后保留DOR信号传导来确定Src对DOR脱敏的贡献。提供这种保护而不干扰内吞作用，但次优内化干扰PP 2保持DOR信号传导的能力，表明激酶的内吞后作用位点。通过证明PP 2抑制Src或siRNA沉默Src增加了内化DORs的膜回收，证实了这一假设，并通过显示莫能菌素或显性负Rab 11（Rab 11 S25 N）抑制再循环消除Src阻断剂防止脱敏的能力进一步证实。最后，Src抑制剂加速了脱敏后DOR-Gα 13偶联的恢复。总之，这些结果表明Src动态调节DOR再循环，并通过这样做有助于这些受体的脱敏。
An important limitation in the clinical use of opiates is progressive loss of analgesic efficacy over time. Development of analgesic tolerance is tightly linked to receptor desensitization. In the case of delta opioid receptors (DOR), desensitization is especially swift because receptors are rapidly internalized and are poorly recycled to the membrane. In the present study, we investigated whether Src activity contributed to this sorting pattern and to functional desensitization of DORs. A first series of experiments demonstrated that agonist binding activates Src and destabilizes a constitutive complex formed by the spontaneous association of DORs with the kinase. Src contribution to DOR desensitization was then established by showing that pre-treatment with Src inhibitor PP2 (20 μM; 1 hr) or transfection of a dominant negative Src mutant preserved DOR signalling following sustained exposure to an agonist. This protection was afforded without interfering with endocytosis, but suboptimal internalization interfered with PP2 ability to preserve DOR signalling, suggesting a post-endocytic site of action for the kinase. This assumption was confirmed by demonstrating that Src inhibition by PP2 or its silencing by siRNA increased membrane recovery of internalized DORs and was further corroborated by showing that inhibition of recycling by monensin or dominant negative Rab11 (Rab11S25N) abolished the ability of Src blockers to prevent desensitization. Finally, Src inhibitors accelerated recovery of DOR-Gαl3 coupling after desensitization. Taken together, these results indicate that Src dynamically regulates DOR recycling and by doing so contributes to desensitization of these receptors.
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影响因子：
4.8
作者：
Ahn, S;Maudsley, S;Daaka, Y
通讯作者：
Daaka, Y
影响因子：
4.8
作者：
Audet, N;Paquin-Gobeil, M;Piñeyro, G
通讯作者：
Piñeyro, G
影响因子：
--
作者：
Fessart, D;Simaan, M;Laporte, SA
通讯作者：
Laporte, SA
DOI：
10.1073/pnas.190276697
发表时间：
2000-09-26
影响因子：
11.1
作者：
DeFea, KA;Vaughn, ZD;Bunnett, NW
通讯作者：
Bunnett, NW
影响因子：
4.8
作者：
Gage, RM;Kim, KA;von Zastrow, M
通讯作者：
von Zastrow, M