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Agonist-dependent mechanism of mu-opioid receptor desensitization.

机译：mu阿片受体脱敏的激动剂依赖性机制。

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摘要

Desensitization of the mu-opioid receptor (MOR) has been implicated as an important regulatory process in the development of tolerance to opiates. Desensitization of G-protein coupled receptor (GPCR) is thought to involve receptor phosphorylation and subsequent recruitment of betaArrestins (betaArrs). However, the roles of receptor phosphorylation and betaArr in morphine-induced MOR desensitization remain to be demonstrated; this may result from the insensitivity of the methods used to study receptor function. Using MOR-induced intracellular Ca2+ ([Ca2+] i) release to monitor receptor activation, [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO) induced MOR desensitization in a receptor phosphorylation- and betaArr-dependent manner. DAMGO-induced desensitization was blunted in HEK293 cells expressing the MORS375A mutant and was eliminated in MEF cells isolated from betaArr2 knockout mice expressing the wild type MOR. However, although morphine induced a more rapid desensitization of [Ca2+]i release than DAMGO did and could induce the phosphorylation of the Ser375 residue of MOR, morphine-induced desensitization was not influenced by mutating MOR phosphorylation sites or in MEF cells lacking betaArr1 and 2. In contrast, morphine induced MOR desensitization via protein kinase C (PKC). By using subtype-specific inhibitors, PKCepsilon was shown to be the PKC subtype activated by morphine and the subtype responsible for morphine-induced desensitization. Meanwhile, DAMGO did not increase PKCepsilon activity and DAMGO-induced MOR desensitization was not affected by a PKCepsilon inhibitor. Among the various proteins within the receptor signaling complex, Galphai2 was phosphorylated by morphine-activated PKCepsilon. Moreover, mutating three putative PKC phosphorylation sites, Ser44, Ser144 and Ser302 on Galphai2 to Ala attenuated morphine-induced, but not DAMGO-induced desensitization. In addition, pretreatment with morphine desensitized cannabinoid receptor CB1 agonist WIN 55212-2-induced [Ca2+]i release, and this desensitization could be reversed by pretreating with a PKCepsilon inhibitor or overexpressing of Galphai2 with the putative PKC phosphorylation sites mutated. Thus, depending on the agonist, activation of MOR could lead to heterologous desensitization and probable crosstalk between MOR and other Galphai-coupled receptors such as the CB1 receptor.
机译：mu阿片受体（MOR）的脱敏被认为是对阿片耐受性发展的重要调控过程。 G蛋白偶联受体（GPCR）的脱敏被认为涉及受体磷酸化和随后的betaArrestins（betaArrs）募集。然而，受体磷酸化和betaArr在吗啡诱导的MOR脱敏中的作用仍有待证明；这可能是由于研究受体功能的方法不灵敏造成的。使用MOR诱导的细胞内Ca2 +（[Ca2 +] i）释放来监测受体激活，[D-Ala2，N-Me-Phe4，Gly5-ol]-脑啡肽（DAMGO）在受体磷酸化和betaArr依赖性的条件下诱导MOR脱敏方式。 DAMGO诱导的脱敏作用在表达MORS375A突变体的HEK293细胞中减弱，在从表达野生型MOR的betaArr2基因敲除小鼠中分离的MEF细胞中消除。然而，尽管吗啡比DAMGO诱导的[Ca2 +] i释放更快的脱敏，并且可以诱导MOR的Ser375残基的磷酸化，但是吗啡诱导的脱敏不受突变的MOR磷酸化位点的影响或在缺少betaArr1和2的MEF细胞中没有受到影响。相反，吗啡通过蛋白激酶C（PKC）诱导MOR脱敏。通过使用亚型特异性抑制剂，PKCepsilon被证明是被吗啡激活的PKC亚型，是负责吗啡诱导的脱敏的亚型。同时，DAMGO不会增加PKCepsilon的活性，并且DAMGO诱导的MOR脱敏不受PKCepsilon抑制剂的影响。在受体信号复合物中的各种蛋白质中，Galphai2被吗啡激活的PKCepsilon磷酸化。此外，将Galphai2上的三个推定的PKC磷酸化位点Ser44，Ser144和Ser302突变为Ala会减弱吗啡诱导的脱敏作用，但不会减弱DAMGO诱导的脱敏作用。此外，用吗啡脱敏的大麻素受体CB1激动剂WIN 55212-2-诱导的[Ca2 +] i释放可通过用PKCepsilon抑制剂预处理或过度表达带有假定的PKC磷酸化位点的Galphai2来逆转。因此，取决于激动剂，MOR的活化可能导致MOR与其他Galphai偶联的受体例如CB1受体之间的异源脱敏和可能的串扰。

著录项

  • 作者

    Chu, Ji.;

  • 作者单位

    University of Minnesota.;

  • 授予单位 University of Minnesota.;
  • 学科 Biology Molecular.;Health Sciences Pharmacology.;Biology Cell.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 193 p.
  • 总页数 193
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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