Src-dependent phosphorylation of μ-opioid receptor at Tyr(336) modulates opiate withdrawal.
Src-dependent phosphorylation of μ-opioid receptor at Tyr(336) modulates opiate withdrawal.
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Mu-阿片受体 Tyr(336) 的 Src 依赖性磷酸化调节阿片戒断
DOI：
10.15252/emmm.201607324
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发表时间：
2017-11
影响因子：
11.1
通讯作者：
Law PY
中科院分区：
文献类型：
--
作者：
Zhang L;Kibaly C;Wang YJ;Xu C;Song KY;McGarrah PW;Loh HH;Liu JG;Law PY
阿片类药物戒断/负强化被认为是从冲动性药物使用发展到强迫性药物使用的机制之一。阿片类药物成瘾的主要假说是成瘾神经回路中细胞内cAMP水平和蛋白激酶A（PKA）活性的增加。这种增加需要在体外长时间阿片剂处理后Src在Tyr 336处磷酸化μ阿片受体（莫尔）。在这里，我们报告Src介导的莫尔在Tyr 336处的磷酸化是小鼠阿片戒断的先决条件。我们观察到在莫尔附近的Src募集和纳洛酮催促戒断期间磷酸化Tyr 336（pY 336）水平的增加。脑室内或立体定向注射Src抑制剂（AZD 0530）或Src shRNA病毒可减弱pY 336水平和几种躯体戒断体征。在Fyn−/−小鼠中也观察到了这一点。将野生型莫尔（而非突变型（Y336 F）莫尔）慢病毒立体定位注射到莫尔−/−小鼠的蓝斑中，恢复了体细胞戒断跳跃。在戒断过程中调节pY 336水平可能是药物开发的未来目标，以防止阿片成瘾行为。
Opiate withdrawal/negative reinforcement has been implicated as one of the mechanisms for the progression from impulsive to compulsive drug use. Increase in the intracellular cAMP level and protein kinase A (PKA) activities within the neurocircuitry of addiction has been a leading hypothesis for opiate addiction. This increase requires the phosphorylation of μ‐opioid receptor (MOR) at Tyr336 by Src after prolonged opiate treatment in vitro. Here, we report that the Src‐mediated MOR phosphorylation at Tyr336 is a prerequisite for opiate withdrawal in mice. We observed the recruitment of Src in the vicinity of MOR and an increase in phosphorylated Tyr336 (pY336) levels during naloxone‐precipitated withdrawal. The intracerebroventricular or stereotaxic injection of a Src inhibitor (AZD0530), or Src shRNA viruses attenuated pY336 levels, and several somatic withdrawal signs. This was also observed in Fyn−/− mice. The stereotaxic injection of wild‐type MOR, but not mutant (Y336F) MOR, lentiviruses into the locus coeruleus of MOR −/− mice restored somatic withdrawal jumping. Regulating pY336 levels during withdrawal might be a future target for drug development to prevent opiate addictive behaviors.