Chronic opioid treatment induces adenylyl cyclase V superactivation - Involvement of G beta gamma
Chronic opioid treatment induces adenylyl cyclase V superactivation - Involvement of G beta gamma
复制标题
DOI：
10.1074/jbc.271.35.21309
复制
发表时间：
1996-08-30
影响因子：
4.8
通讯作者：
Vogel, Z
中科院分区：
文献类型：
--
作者：
AvidorReiss, T;Nevo, I;Vogel, Z
众所周知，用阿片类药物慢性治疗神经细胞和组织，与其急性作用相反，会导致cAMP积聚增加。这种现象被定义为腺酰环化酶过度激活，已被认为与阿片成瘾有关，但其诱导机制尚不清楚。在这里，我们表明，这一现象可以在COS-7细胞中复制和研究，共转染腺苷酸环化酶V型和u-阿片受体cDNA。这些细胞表现出对腺酰环化酶活性的急性阿片类抑制，而长期暴露于Mu激动剂吗啡或[D-Ala(2)，N-甲基-Phe(4)，Gly-ol(5)]脑啡肽则导致腺酰环化酶时间依赖性的过度激活。这种超激活状态是可逆的，因为它在激动剂停用后逐渐消失，腺酰环化酶超激活可以通过百日咳毒素预处理来阻止，这表明G(I/O)蛋白的参与，或者通过与β-肾上腺素能受体激酶的羧基末端或与α-转导蛋白(G(β-伽马)二聚体的清除剂)的共转染，表明G蛋白β-伽马二聚体在腺酰环化酶超激活中的作用。然而，与其他几种依赖G(β-γ)的信号转导机制(如细胞外信号调节激酶2/MAP激酶途径)相反，腺苷环化酶的过度激活不受HAS显性阴性突变体N17-RAS的影响。
It has been known for some time that chronic treatment of neuronal cells and tissues with opioids, contrary to their acute effect, leads to an increase in cAMP accumulation. This phenomenon, defined as adenylyl cyclase superactivation, has been implicated in opiate addiction, yet the mechanism by which it is induced remains unclear. Here, we show that this phenomenon can be reproduced and studied in COS-7 cells cotransfected with adenylyl cyclase type V and mu-opioid receptor cDNAs. These cells display acute opioid inhibition of adenylyl cyclase activity, whereas prolonged exposure to the mu-agonist morphine or [D-Ala(2), N-methyl-Phe(4), Gly-ol(5)]enkephalin leads to a time-dependent superactivation of adenylyl cyclase. This superactivated state is reversible, because it is gradually lost following agonist withdrawal, Adenylyl cyclase superactivation can be prevented by pertussis toxin pretreatment, indicating the involvement of G(i/o) proteins, or by cotransfection with the carboxyl terminus of beta-adrenergic receptor kinase or with alpha-transducin (scavengers of G(beta gamma) dimers), indicating a role for the G protein beta gamma dimers in adenylyl cyclase superactivation. However, contrary to several other G(beta gamma)-dependent signal transduction mechanisms (e.g. the extracellular signal-regulated kinase 2/MAP kinase pathway), adenylyl cyclase superactivation is not affected by the Has dominant negative mutant N17-Ras.