GRK2 Constitutively Governs Peripheral Delta Opioid Receptor Activity
GRK2 Constitutively Governs Peripheral Delta Opioid Receptor Activity
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DOI：
10.1016/j.celrep.2016.07.084
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发表时间：
2016-09-06
期刊：
影响因子：
8.8
通讯作者：
Jeske, Nathaniel A.
中科院分区：
文献类型：
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作者：
Brackley, Allison Doyle;Gomez, Ruben;Jeske, Nathaniel A.
阿片类药物仍然是镇痛治疗的标准;然而，全身治疗的不良反应禁忌长期给药。虽然大多数临床阿片类药物靶向μ阿片受体（莫尔），但靶向δ类（DOR）的阿片类药物也显示出镇痛功效。此外，外周限制性阿片类药物代表了镇痛的一个有吸引力的方向。然而，包括DOR在内的阿片受体在没有炎症的情况下不能镇痛。在这里，我们报告了G蛋白偶联受体激酶2（GRK 2）与外周感觉神经元中的质膜DOR天然结合，以抑制镇痛激动剂的功效。这种相互作用阻止了G β亚基与受体的最佳结合，从而降低了DOR活性。重要的是，缓激肽刺激GRK 2运动远离DOR和Raf激酶抑制蛋白（RKIP）。蛋白激酶C（PKC）依赖性RKIP磷酸化诱导GRK 2隔离，恢复感觉神经元中的DOR功能。总之，这些结果扩展了GRK 2的已知功能，确定了维持外周DOR处于镇痛功能不全状态的非内化作用。
Opioids remain the standard for analgesic care; however, adverse effects of systemic treatments contraindicate long-term administration. While most clinical opioids target mu opioid receptors (MOR), those that target the delta class (DOR) also demonstrate analgesic efficacy. Furthermore, peripherally restrictive opioids represent an attractive direction for analgesia. However, opioid receptors including DOR are analgesically incompetent in the absence of inflammation. Here, we report that G protein-coupled receptor kinase 2 (GRK2) naively associates with plasma membrane DOR in peripheral sensory neurons to inhibit analgesic agonist efficacy. This interaction prevents optimal G beta subunit association with the receptor, thereby reducing DOR activity. Importantly, bradykinin stimulates GRK2 movement away from DOR and onto Raf kinase inhibitory protein (RKIP). protein kinase C (PKC)-dependent RKIP phosphorylation induces GRK2 sequestration, restoring DOR functionality in sensory neurons. Together, these results expand the known function of GRK2, identifying a non-internalizing role to maintain peripheral DOR in an analgesically incompetent state.