Molecular mechanisms of agonist-induced desensitization of the cloned mouse kappa opioid receptor.
Molecular mechanisms of agonist-induced desensitization of the cloned mouse kappa opioid receptor.
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发表时间：
1994-09
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通讯作者：
K. Raynor;H. Kong;J. Hines;G. Kong;J. Benovic;K. Yasuda;G. Bell;T. Reisine
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作者：
K. Raynor;H. Kong;J. Hines;G. Kong;J. Benovic;K. Yasuda;G. Bell;T. Reisine
阿片受体长时间暴露于激动剂可导致脱敏，这是一种与耐受性相关的细胞事件。尽管存在μ和δ阿片受体脱敏的证据，但关于κ阿片受体的体外调节的信息少得多，因为不存在特异性表达这类阿片受体的细胞系。最近，我们克隆了小鼠κ阿片受体。在COS-7细胞中表达后，该蛋白表现出κ 1受体的药理学特异性，并介导cAMP形成的激动剂抑制。将表达κ受体的COS-7细胞连续暴露于激动剂反式-（+/-）-3，4-二氯-N-甲基-N-[2-（1-吡咯烷基）-环己基]-苯乙酰胺甲磺酸盐（U 50，488），降低了κ选择性激动剂[3 H] U69，593的特异性结合。此外，U 50，488抑制阿片拮抗剂[3 H]纳洛酮与κ受体结合的效力降低。然而，[3 H]纳洛酮的总特异性结合没有改变，表明短期（2-4小时）激动剂处理κ受体降低了受体对激动剂的亲和力，但没有降低κ受体的密度。kappa受体对激动剂亲和力的降低取决于激动剂暴露的时间，并且是可逆的。受体对激动剂的亲和力降低与κ受体脱敏有关，因为在用U 50，488预处理的细胞中，κ受体介导的cAMP形成抑制作用丧失。κ受体的脱敏依赖于激动剂处理的时间和浓度，被κ选择性拮抗剂nor-binaltorphimine阻断，并且是可逆的。（250字处删节）
Prolonged exposure of opioid receptors to agonists can cause desensitization, a cellular event linked to tolerance. Although evidence exists for mu and delta opioid receptor desensitization, much less information is available concerning the in vitro regulation of kappa opioid receptors because no cell lines exist that specifically express this class of opioid receptor. Recently we have cloned the mouse kappa opioid receptor. After expression in COS-7 cells, this protein exhibits the pharmacological specificity of a kappa 1 receptor and mediates agonist inhibition of cAMP formation. Continuous exposure of COS-7 cells expressing the kappa receptor to the agonist trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]- benzeneacetamide methanesulfonate salt (U50,488) reduces the specific binding of the kappa-selective agonist [3H]U69,593. Furthermore, the potency of U50,488 to inhibit the binding of the opiate antagonist [3H]naloxone to the kappa receptor is reduced. However, total specific binding of [3H]naloxone is not altered, indicating that short-term (2-4 hr) agonist treatment of the kappa receptor reduces the affinity of the receptor for agonists but does not reduce the density of kappa receptors. The reduction in affinity of the kappa receptor for agonists is dependent on the time of agonist exposure and is reversible. The reduced affinity of the receptor for agonists is associated with kappa receptor desensitization, because kappa receptor-mediated inhibition of cAMP formation is lost in cells pretreated with U50,488. The desensitization of the kappa receptor is dependent on the time and concentration of agonist treatment, is blocked by the kappa-selective antagonist nor-binaltorphimine and is reversible.(ABSTRACT TRUNCATED AT 250 WORDS)