Preformed vs. on-demand: molecular economics of endocannabinoid signalling.
Preformed vs. on-demand: molecular economics of endocannabinoid signalling.
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预制与按需：内源性大麻素信号传导的分子经济学。
DOI：
10.1113/jphysiol.2013.262717
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发表时间：
2013
期刊：
影响因子：
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通讯作者：
Frazier,CharlesJ
中科院分区：
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作者：
Frazier,CharlesJ
内源性大麻素是一种强大的逆行递质，在哺乳动物中枢神经系统的许多区域调节突触传递。内源性大麻素介导的逆行传递可由突触后钙内流、突触后激活GQ/11偶联的代谢性受体或这些刺激的组合而诱导。一旦动员起来，内源性大麻素就会向后穿过突触间隙，在那里它们通过激活Gi/o偶联的突触前I型大麻受体(CB1Rs)来抑制递质释放。在过去的10-15年里，人们对内源性大麻素介导的信号系统的性质、多样性、效力和治疗潜力有了大量的了解。然而，在这段时间里，一些问题比其他问题更顽固，而且可能经常发生的情况是，一些来之不易的答案本身就产生了新的紧迫问题。一个很好的例子与内源性大麻素的分子特性有关，在CB1R介导的突触可塑性的大多数经典形式中，内源性大麻素充当逆行信使。此时，现有的最佳证据将表明答案是2-花生四烯基甘油(2-AG)。支持这一结论的最有力的数据来自最近的一系列研究，这些研究依赖于二酰甘油脂肪酶(DAGL)的基因缺失，DAGL是合成2-AG所必需的酶。事实上，三个独立的实验室开发了DAGLα基因敲除动物，所有实验室都观察到基本上完全丧失了CB1R介导的短期突触可塑性，共同作用于广泛的大脑区域，包括海马体、小脑、纹状体和前额皮质(Gao等人)。2010年；田村等人。2010年；Yoshino等人。令人惊讶的是，这一时期的工作令人惊讶的是，一系列依赖DAGL急性药理抑制的平行研究产生了一套复杂的、高度不一致的结果。因此，提出了一个新的问题：如果2-AG实际上是大多数经典形式的CB1R依赖信号所需的逆行信使，正如研究一贯表明的那样，从基因上移除一种关键的合成酶，为什么对同一种酶的急性药物抑制有时如此无效？为了解决这个问题，几位研究人员提出，可能存在一个预先形成的2-AG池，它以DAGL依赖的方式合成，但然后储存在神经元中，供以后DAGL独立释放(例如，见Minet al。2010年；Alger&Kim，2011年)。虽然这一假设有效地解决了遗传研究和部分药理学结果之间存在的尖锐差异，但它并没有直接解决各种药理学研究本身之间的不一致。此外，它还挑战了一个长期持有的假说，即内源性大麻素是按需合成和释放的，这一可能性更容易与其极端亲脂的性质相一致，从而使其成为膜的意思。最终，为了使该领域更全面地接受预先形成的池假说，可能需要对合成后2-AG如何在没有DAGL的情况下进行存储和选择性动员进行更详细和更机械的理解。相反，为了更全面地拒绝预成池假说，在大量研究中，更好地理解为什么急性应用DAGL抑制剂未能阻断CB1R依赖的信号转导将有助于更好地理解。
Endogenous cannabinoids are powerful retrograde transmitters that modulate synaptic transmission in many areas of the mammalian CNS. Endocannabinoidmediated retrograde transmission can be induced by postsynaptic calcium influx, by postsynaptic activation of specific Gq/11-coupled metabotropic receptors, or by a combination of such stimuli. Once mobilized, endocannabinoids travel backwards across the synaptic cleft where they inhibit transmitter release via activation of Gi/o-coupled presynaptic type I cannabinoid receptors (CB1Rs). Over the last 10–15 years, an enormous amount has been learned about the nature, diversity, power and therapeutic potential of endocannabinoid-mediated signalling systems. However, over that time, some questions have been more persistent than others have, and as is perhaps often the case, some hard won answers have generated new and pressing questions of their own. A good case in point has to do with the molecular identity of the endogenous cannabinoid that acts as a retrograde messenger in most classic forms of CB1R-mediated synaptic plasticity. At this time, the best available evidence would indicate that the answer is 2-arachidonoylglycerol (2-AG). The strongest data supporting that conclusion comes from a recent series of studies that rely on genetic deletion of diacylglycerol lipase (DAGL), an enzyme necessary for the synthesis of 2-AG. Indeed, three laboratories independently developed DAGLα knockout animals and all observed essentially complete loss of CB1R-mediated short-term synaptic plasticity, collectively across a wide variety of brain areas, including the hippocampus, cerebellum, striatum and prefrontal cortex (Gao et al. 2010; Tanimura et al. 2010; Yoshino et al. 2011).What is surprising about work during this period is that a series of parallel studies relying on acute pharmacological inhibition of DAGL produced a complex set of highly inconsistent results. Thus was raised a new question: If 2-AG is in fact the retrograde messenger required for most classic forms of CB1R-dependent signalling, as is consistently indicated by studies that genetically remove a key synthetic enzyme, why is acute pharmacological inhibition of the same enzyme sometimes so ineffective? In an effort to address this question, several investigators proposed that there may exist a pre-formed pool of 2-AG that is synthesized in a DAGL-dependent fashion, but then stored in neurons for later DAGL independent release (eg see Minet al. 2010; Alger & Kim, 2011). While this hypothesis effectively addresses a sharp disparity that exists between the genetic studies and a subset of the pharmacological results, it does not directly address the inconsistencies between various pharmacological studies themselves. Further, it also challenges a long held hypothesis that endogenous cannabinoids are synthesized and released on-demand, a possibility that is much easier to reconcile with their extremely lipophilic and thus membrane permeant nature. Ultimately, for the field to embrace the preformed pool hypothesis more fully, it will probably be necessary to develop a more detailed and mechanistic understanding of exactly how, once synthesized, 2-AG may be stored and selectively mobilized without DAGL. By contrast, to reject the preformed pool hypothesis more fully, it would be helpful to develop a better understanding of why acute application of DAGL inhibitors has failed to block CB1R-dependent signalling in a significant number of studies.