Kinase cascades and ligand-directed signaling at the kappa opioid receptor.
Kinase cascades and ligand-directed signaling at the kappa opioid receptor.
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DOI：
10.1007/s00213-010-1806-y
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发表时间：
2010-06
影响因子：
3.4
通讯作者：
Chavkin, Charles
中科院分区：
文献类型：
--
作者：
Bruchas, Michael R.;Chavkin, Charles
关键词：
强啡肽/κ-阿片受体（KOR）系统被认为是应激反应的关键组成部分。众所周知，强啡肽-KOR的应激诱导的激活产生镇痛，并且最近它被认为是应激诱导的反应的介体，包括焦虑、抑郁和药物寻求的恢复。选择性靶向特定KOR信号通路的药物可能被证明是治疗情绪和成瘾性疾病的潜在有用药物。KOR是七跨膜（7 TM）G蛋白偶联受体（GPCR）超家族成员。百日咳毒素敏感性G蛋白的KOR激活导致Gαi/o抑制腺苷酸环化酶产生cAMP并释放Gβγ，其调节Ca+2和K+通道的电导。此外，KOR激动剂激活激酶级联，包括G蛋白偶联受体激酶（GRK）和促分裂原活化蛋白激酶（MAPK）家族的成员：ERK 1/2、p38和JNK。最近的药理学数据表明，GPCR作为动态的、多构象的蛋白质复合物存在，其可以被特定的配体导向不同的信号传导途径。配体诱导的KOR构象引起β-arrestin依赖性p38 MAPK激活，导致厌恶;而配体诱导的激活JNK而不激活arrestin的构象产生KOR信号转导的持久失活。在这篇综述中，我们讨论了KOR信号转导研究的现状和支持两个新假设的数据：1）不能有效激活p38 MAPK的KOR选择性部分激动剂可能是有用的镇痛剂，而不会产生选择性的焦虑或致幻作用，高效的KOR激动剂和2）不激活JNK的KOR拮抗剂可能是有效的短效药物，可以促进应激恢复。
The dynorphin / kappa-opioid receptor (KOR) system has been implicated as a critical component of the stress response. Stress-induced activation of dynorphin-KOR is well-known to produce analgesia, and more recently it has been implicated as a mediator of stress-induced responses including anxiety, depression, and reinstatement of drug seeking. Drugs selectively targeting specific KOR signaling pathways may prove potentially useful as therapeutic treatments for mood and addiction disorders. KOR is a member of the seven transmembrane spanning (7TM) G-protein coupled receptor (GPCR) superfamily. KOR activation of pertussis toxin-sensitive G proteins leads to Gαi/o inhibition of adenylyl cyclase production of cAMP and releases Gβγ, which modulates the conductances of Ca+2 and K+ channels. In addition, KOR agonists activate kinase cascades including G-protein coupled Receptor Kinases (GRK) and members of the mitogen-activated protein kinase (MAPK) family: ERK1/2, p38 and JNK. Recent pharmacological data suggests that GPCRs exist as dynamic, multi-conformational protein complexes that can be directed by specific ligands towards distinct signaling pathways. Ligand-induced conformations of KOR that evoke β–arrestin-dependent p38 MAPK activation result in aversion; whereas ligand-induced conformations that activate JNK without activating arrestin produce long-lasting inactivation of KOR signaling. In this review, we discuss the current status of KOR signal transduction research and the data that support two novel hypotheses: 1) KOR selective partial agonists that do not efficiently activate p38 MAPK may be useful analgesics without producing the dysphoric or hallucinogenic effects of selective, highly efficacious KOR agonists and 2) KOR antagonists that do not activate JNK may be effective short-acting drugs that may promote stress-resilience.
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