Daniel H, Rancillac A, Crepel F
Neurobiologie des Processus Adaptatifs-UMR CNRS 7102-UPMC, Laboratoire de Neurobiologie et Pharmacologie de la Synapse-case n 8, 7 quai St Bernard, 75005 Paris, France.
J Physiol. 2004 May 15;557(Pt 1):159-74. doi: 10.1113/jphysiol.2004.063263. Epub 2004 Mar 19.
Activation of CB1 cannabinoid receptors in the cerebellum acutely depresses excitatory synaptic transmission at parallel fibre-Purkinje cell synapses by decreasing the probability of glutamate release. This depression involves the activation of presynaptic 4-aminopyridine-sensitive K(+) channels by CB1 receptors, which in turn inhibits presynaptic Ca(2+) influx controlling glutamate release at these synapses. Using rat cerebellar frontal slices and fluorometric measures of presynaptic Ca(2+) influx evoked by stimulation of parallel fibres with the fluorescent dye fluo-4FF, we tested whether the CB1 receptor-mediated inhibition of this influx also involves a direct inhibition of presynaptic voltage-gated calcium channels. Since various physiological effects of CB1 receptors appear to be mediated through the activation of PTX-sensitive proteins, including inhibition of adenylate cyclases, activation of mitogen-activated protein kinases (MAPK) and activation of G protein-gated inwardly rectifying K(+) channels, we also studied the potential involvement of these intracellular signal transduction pathways in the cannabinoid-mediated depression of presynaptic Ca(2+) influx. The present study demonstrates that the molecular mechanisms underlying the CB1 inhibitory effect involve the activation of the PTX-sensitive G(i)/G(o) subclass of G proteins, independently of any direct effect on presynaptic Ca(2+) channels (N, P/Q and R (SNX-482-sensitive) types) or on adenylate cyclase or MAPK activity, but do require the activation of G protein-gated inwardly rectifying (Ba(2+)- and tertiapin Q-sensitive) K(+) channels, in addition to 4-aminopyridine-sensitive K(+) channels.
小脑内CB1大麻素受体的激活通过降低谷氨酸释放的概率，急性抑制平行纤维-浦肯野细胞突触处的兴奋性突触传递。这种抑制作用涉及CB1受体对突触前4-氨基吡啶敏感的钾通道的激活，进而抑制控制这些突触处谷氨酸释放的突触前钙离子内流。利用大鼠小脑额叶切片以及用荧光染料fluo-4FF刺激平行纤维诱发的突触前钙离子内流的荧光测定法，我们测试了CB1受体介导的对这种内流的抑制是否也涉及对突触前电压门控钙通道的直接抑制。由于CB1受体的各种生理效应似乎是通过激活对百日咳毒素敏感的蛋白质介导的，包括抑制腺苷酸环化酶、激活丝裂原活化蛋白激酶（MAPK）以及激活G蛋白门控内向整流钾通道，我们还研究了这些细胞内信号转导途径在大麻素介导的突触前钙离子内流抑制中的潜在作用。本研究表明，CB1抑制作用的分子机制涉及对百日咳毒素敏感的G蛋白G(i)/G(o)亚类的激活，与对突触前钙通道（N、P/Q和R（SNX-482敏感）型）、腺苷酸环化酶或MAPK活性的任何直接作用无关，但除了4-氨基吡啶敏感的钾通道外，确实需要激活G蛋白门控内向整流（钡离子和替他品Q敏感）钾通道。
