Estrogen Regulation of GRK2 Inactivates Kappa Opioid Receptor Signaling Mediating Analgesia, But Not Aversion
Estrogen Regulation of GRK2 Inactivates Kappa Opioid Receptor Signaling Mediating Analgesia, But Not Aversion
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DOI：
10.1523/jneurosci.0653-18.2018
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发表时间：
2018-09-12
影响因子：
5.3
通讯作者：
Chavkin, Charles
中科院分区：
文献类型：
--
作者：
Abraham, Antony D.;Schattauer, Selena S.;Chavkin, Charles
kappa阿片受体（KORs）的激活通过不同的细胞内信号通路产生镇痛和厌恶，但是G蛋白偏倚的KOR激动剂是否可以设计成具有临床效用将取决于对所涉及的信号机制的更好理解。我们发现，在雄性和雌性C57BL/6N小鼠中，KOR激活产生条件性场所厌恶和增强的可卡因CPP。与此一致的是，男性和女性在KOR激活后都表现出抑制素介导的磷酸化p38 MAPK的增加。然而，与男性不同的是，在女性中，KOR激活具有不一致的镇痛作用，并且在男性中，KOR增加了G β - γ介导的ERK磷酸化，而在女性中则没有。在女性中，KOR脱敏不是缺乏反应的原因，因为Grk3和Pdyn基因敲除都没有增强镇痛。相反，反应性依赖于发情周期，因为在周期的低雌激素期和卵巢切除（OVX）女性中，KOR镇痛很明显。雌二醇治疗OVX女性抑制KOR介导的镇痛，表明雌二醇足以钝化G β - γ介导的KOR信号。已知G蛋白偶联受体激酶2 （GRK2）调节ERK的激活，我们发现GRK2的抑制性，磷酸化形式在完整的雌性中明显更高。CMPD101对GRK2/3的抑制增加了女性对磷酸化erk的KOR刺激，降低了KOR介导的多巴胺释放抑制的性别差异，增强了女性的mu阿片受体和KOR介导的镇痛作用。在OVX女性中，雌二醇增加了GRK2和G β γ之间的联系。这些研究表明，雌二醇通过增加GRK2的磷酸化和GRK2可能对G β γ的隔离，减弱了G蛋白介导的信号。
Activation of kappa opioid receptors (KORs) produces analgesia and aversion via distinct intracellular signaling pathways, but whether G protein-biased KOR agonists can be designed to have clinical utility will depend on a better understanding of the signaling mechanisms involved. We found that KOR activation produced conditioned place aversion and potentiated CPP for cocaine in male and female C57BL/6N mice. Consistent with this, males and females both showed arrestin-mediated increases in phospho-p38 MAPK following KOR activation. Unlike in males, however, KOR activation had inconsistent analgesic effects in females and KOR increased G beta gamma-mediated ERK phosphorylation in males, but not females. KOR desensitization was not responsible for the lack of response in females because neither Grk3 nor Pdyn gene knock-out enhanced analgesia. Instead, responsiveness was estrous cycle dependent because KOR analgesia was evident during low estrogen phases of the cycle and in ovariectomized (OVX) females. Estradiol treatment of OVX females suppressed KOR-mediated analgesia, demonstrating that estradiol was sufficient to blunt G beta gamma-mediated KOR signals. G protein-coupled receptor kinase 2 (GRK2) is known to regulate ERK activation, and we found that the inhibitory, phosphorylated form of GRK2 was significantly higher in intact females. GRK2/3 inhibition by CMPD101 increased KOR stimulation of phospho-ERK in females, decreased sex differences in KOR-mediated inhibition of dopamine release, and enhanced mu opioid receptor and KOR-mediated analgesia in females. In OVX females, estradiol increased the association between GRK2 and G beta gamma. These studies suggest that estradiol, through increased phosphorylation of GRK2 and possible sequestration of G beta gamma by GRK2, blunts G protein-mediated signals.