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首页> 外文期刊>Cellular Signalling >RGS14 prevents morphine from internalizing Mu-opioid receptors in periaqueductal gray neurons
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RGS14 prevents morphine from internalizing Mu-opioid receptors in periaqueductal gray neurons

机译：RGS14阻止吗啡使导水管周围灰色神经元内的Mu阿片受体内在化

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摘要

Opioid agonists display different capacities to stimulate mu-opioid receptor (MOR) endocytosis, which is related to their ability to provoke the phosphorylation of specific cytosolic residues in the MORs. Generally, opioids that efficiently promote MOR endocytosis and recycling produce little tolerance, as is the case for [D-Ala(2), N-MePhe(4),Gly-ol(5)] encephalin (DAMGO). However, morphine produces rapid and profound antinociceptive desensitization in the adult mouse brain associated with little MOR internalization. The regulator of G-protein signaling, the RGS14 protein, associates with MORs in periaqueductal gray matter (PAG) neurons, and when RGS14 is silenced morphine increased the serine 375 phosphorylation in the C terminus of the MOR, a GRK substrate. Subsequently, these receptors were internalized and recycled back to the membrane where they accumulated on cessation of antinociception. These mice now exhibited a resensitized response to morphine and little tolerance developed. Thus, in morphine-activated MORs the RGS14 prevents GRKs from phosphorylating those residues required for beta-arresting-mediated endocytosis. Moreover morphine but not DAMGO triggered a process involving calcium/calmodulin-dependent kinase II (CaMKII) in naive mice, which contributes to MOR desensitization in the plasma membrane. In RGS14 knockdown mice morphine failed to activate this kinase. It therefore appears that phosphorylation and internalization of MORs disrupts the CaMKII-mediated negative regulation of these opioid receptors. (C) 2007 Elsevier Inc. All rights reserved.
机译：阿片激动剂显示出不同的刺激阿片受体（MOR）内吞能力，这与它们在MOR中引起特定胞质残基磷酸化的能力有关。通常，有效促进MOR内吞和再循环的阿片类药物几乎没有产生耐受性，就像[D-Ala（2），N-MePhe（4），Gly-ol（5）]脑啡肽（DAMGO）那样。但是，吗啡在成年小鼠大脑中产生快速而深刻的抗伤害感受性脱敏作用，而几乎没有MOR内部化。 G蛋白信号的调节剂RGS14蛋白与导水管周围灰质（PAG）神经元中的MOR相关，当RGS14沉默时，吗啡会增加MOR的C端（GRK底物）的丝氨酸375磷酸化。随后，这些受体被内化并循环回到膜，在它们停止抗伤害感受后在膜上积聚。这些小鼠现在对吗啡表现出敏化反应，几乎没有耐受性。因此，在吗啡激活的MOR中，RGS14阻止GRK磷酸化β-逮捕介导的胞吞作用所需的那些残基。此外，吗啡而不是DAMGO触发了幼稚小鼠体内涉及钙/钙调蛋白依赖性激酶II（CaMKII）的过程，该过程导致质膜中的MOR脱敏。在RGS14敲低小鼠中，吗啡未能激活该激酶。因此，似乎MOR的磷酸化和内在化破坏了CaMKII介导的这些阿片受体的负调节。 （C）2007 Elsevier Inc.保留所有权利。

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