Department of Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem, NC 27157, USA.
CNS Neurol Disord Drug Targets. 2009 Dec;8(6):422-31. doi: 10.2174/187152709789824615.
The endocannabinoids anandamide and 2-arachidonoylglycerol are lipid mediators that signal via CB(1) and CB(2) cannabinoid receptors and Gi/o-proteins to inhibit adenylyl cyclase and stimulate mitogen-activated protein kinase. In the brain, CB(1) receptors interact with opioid receptors in close proximity, and these receptors may share G-proteins and effector systems. In the striatum, CB(1) receptors function in coordination with D(1) and D(2) dopamine receptors, and combined stimulation of CB(1)-D(2) receptor heteromeric complexes promotes a unique interaction to stimulate cAMP production. CB(1) receptors also trigger growth factor receptor signaling cascades in cells by engaging in cross-talk or interreceptor signal transmission with the receptor tyrosine kinase (RTK) family. Mechanisms for CB(1) receptor-RTK transactivation can include stimulation of signal transduction pathways regulated by second messengers such as phospholipase C, metalloprotease cleavage of membrane-bound precursor proteins such as epidermal growth factor which activate RTKs, RTK autophosphorylation, and recruitment of non-receptor tyrosine kinases. CB(1) and CB(2) receptors are expressed in peripheral tissues including liver and adipose tissue, and are induced in pathological conditions. Novel signal transduction resulting from endocannabinoid regulation of AMP-regulated kinase and peroxisome proliferator-activated receptors have been discovered from studies of hepatocytes and adipocytes. It can be predicted that drug discovery of the future will be based upon these novel signal transduction mechanisms for endocannabinoid mediators.
内源性大麻素大麻素受体配体——花生四烯酸乙醇胺和 2-花生四烯酰甘油，通过与 CB1 和 CB2 大麻素受体以及 Gi/o 蛋白相互作用，抑制腺苷酸环化酶和刺激丝裂原活化蛋白激酶来传递信号。在大脑中，CB1 受体与阿片受体近距离相互作用，这些受体可能共享 G 蛋白和效应系统。在纹状体中，CB1 受体与 D1 和 D2 多巴胺受体协同作用，而 CB1-D2 受体异源二聚体的联合刺激则促进独特的相互作用以刺激 cAMP 的产生。CB1 受体还通过与受体酪氨酸激酶（RTK）家族的交叉对话或受体间信号转导与细胞中的生长因子受体信号级联相互作用。CB1 受体-RTK 反式激活的机制可以包括通过第二信使如磷脂酶 C 调节的信号转导途径的刺激、表皮生长因子等膜结合前体蛋白的金属蛋白酶切割以激活 RTKs、RTK 自身磷酸化以及非受体酪氨酸激酶的募集。CB1 和 CB2 受体在外周组织（包括肝脏和脂肪组织）中表达，并在病理条件下诱导。从肝细胞和脂肪细胞的研究中发现了内源性大麻素调节 AMP 激活的蛋白激酶和过氧化物酶体增殖物激活受体的新型信号转导。可以预测，未来的药物发现将基于内源性大麻素介质的这些新型信号转导机制。
