Functionally selective cannabinoid receptor signalling: Therapeutic implications and opportunities
Functionally selective cannabinoid receptor signalling: Therapeutic implications and opportunities
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DOI：
10.1016/j.bcp.2010.02.013
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发表时间：
2010-07-01
影响因子：
5.8
通讯作者：
Lambert, Didier M.
中科院分区：
文献类型：
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作者：
Bosier, Barbara;Muccioli, Giulio G.;Lambert, Didier M.
CBI和CB2受体是G蛋白偶联受体(GPCRs)，可被多种内源性配体识别，并激活多条信号通路。这种多种多样的配体和细胞内转导机制支持内源性大麻素系统对生理功能的复杂控制，但需要对受体激活时触发的信号事件进行微调调节。在这里，我们回顾了由大麻素受体激活的不同的信号通路，并讨论了允许由内源性或外源性配体触发的相关功能反应的特异性的机制。与经典的概念不同的是，在给定的GPCR中，所有激动剂在所有组织中都会诱导类似的下游事件，我们还总结了支持大麻素受体上存在功能选择性和蛋白质激动剂的实验证据。通过强调受体-G蛋白偶联的配体或构成活性依赖的规范，这些概念解释了不同的大麻素配体如何激活特定的下游介质。最后，尽管大麻素类信号的多样性和特异性现在已经在体外建立，但从体内研究中获得的数据很少。因此，我们通过检验支持这种复杂性在大麻素系统中的生理学相关性的实验证据来总结这篇综述。通过激活已定义的信号级联，有选择地操纵生理功能的能力将极有可能有助于开发各种适应症的有效和安全的大麻类药物。(C)2010 Elsevier Inc.保留所有权利。
The CBI and CB2 cannabinoid receptors are G protein-coupled receptors (GPCRs) recognized by a variety of endogenous ligands and activating multiple signalling pathways. This multiplicity of ligands and intracellular transduction mechanisms supports a complex control of physiological functions by the endocannabinoid system, but requires a finely tuned regulation of the signalling events triggered on receptor activation. Here we review the diverse signalling pathways activated by the cannabinoid receptors and discuss the mechanisms allowing for specificity in the associated functional responses triggered by endogenous or exogenous ligands. At variance with the classical concept that all agonists at a given GPCR induce a similar repertoire of downstream events in all tissues, we also summarize the experimental evidence supporting the existence of functional selectivity and protean agonism at cannabinoid receptors. By placing emphasis on the ligand- or constitutive activity-dependent specifications of receptor-G protein coupling, these concepts explain how distinct cannabinoid ligands may activate specific downstream mediators. Finally, although both the diversity and specificity in cannabinoid signalling are now established in vitro, few data are available from in vivo studies. Therefore, we conclude this review by examining the experimental evidence supporting the physiological relevance of this complexity in the cannabinoid system. The ability to selectively manipulate physiological functions, through activation of defined signalling cascades, will in all likelihood help in the development of efficacious and safe cannabinoid-based therapeutics for a variety of indications. (C) 2010 Elsevier Inc. All rights reserved.