Molecular mechanisms for heterologous sensitization of adenylate cyclase
Molecular mechanisms for heterologous sensitization of adenylate cyclase
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DOI：
10.1124/jpet.302.1.1
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发表时间：
2002-07-01
影响因子：
3.5
通讯作者：
Watts, VJ
中科院分区：
文献类型：
--
作者：
Watts, VJ
腺苷酸环化酶（EC 4.6.1.1）的九种膜结合亚型受到神经递质和药物的高度调节，所述神经递质和药物通过G蛋白偶联受体起作用以调节细胞内cAMP水平。一般而言，Ga（s）偶联受体的急性激活刺激cAMP积累，而Ga（i/o）偶联受体的急性激活通常抑制cAMP积累。还充分确定的是，G蛋白偶联受体的持续活化将改变随后的药物调节的cAMP积累。这些变化被认为是代表细胞适应性反应后，长期受体激活。一种常见的现象是腺苷酸环化酶的异源致敏，其特征是在持续激活Galalpha（i/o）偶联受体后对药物刺激的cAMP积累的反应性增强。腺苷酸环化酶的异源致敏最初被提出来解释慢性阿片给药后的耐受性和戒断，并且可能是细胞适应抑制性受体的长期激活的机制。有人认为，这种适应机制在许多滥用药物成瘾和戒断过程中以及在包括精神分裂症和抑郁症在内的精神疾病中发挥作用。虽然确切的机制仍然未知，在过去的十年中的研究已经导致了进展，了解与细胞模型中的重组和内源性腺苷酸环化酶的异源致敏相关的分子事件。这些事件包括与异源致敏发生相关的百日咳毒素敏感事件和最近发现的与异源致敏表达相关的Ga依赖性事件。
The nine membrane-bound isoforms of the enzyme adenylate cyclase (EC 4.6.1.1) are highly regulated by neurotransmitters and drugs acting through G protein-coupled receptors to modulate intracellular cAMP levels. In general, acute activation of Galpha(s)-coupled receptors stimulates cAMP accumulation, whereas acute activation of Galpha(i/o)-coupled receptors typically inhibits cAMP accumulation. It is also well established that persistent activation of G-protein coupled receptors will alter subsequent drug-modulated cAMP accumulation. These alterations are thought to represent cellular adaptive responses following prolonged receptor activation. One phenomenon commonly observed, heterologous sensitization of adenylate cyclase, is characterized by an enhanced responsiveness to drug-stimulated cAMP accumulation following persistent activation of Galpha(i/o)-coupled receptors. Heterologous sensitization of adenylate cyclase was originally proposed to explain tolerance and withdrawal following chronic opiate administration and may be a mechanism by which cells adapt to prolonged activation of inhibitory receptors. Such an adaptive mechanism has been suggested to play a role in the processes of addiction to and withdrawal from many drugs of abuse and in psychiatric disorders including schizophrenia and depression. Although the precise mechanisms remain unknown, research over the last decade has led to advances toward understanding the molecular events associated with heterologous sensitization of recombinant and endogenous adenylate cyclases in cellular models. These events include the pertussis toxin-sensitive events that are associated with the development of heterologous sensitization and the more recently identified Galpha(s)-dependent events that are involved in the expression of heterologous sensitization.