| First Author | Hashimotodani Y | Year | 2013 |
| Journal | J Physiol | Volume | 591 |
| Issue | 19 | Pages | 4765-76 |
| PubMed ID | 23858009 | Mgi Jnum | J:214176 |
| Mgi Id | MGI:5588528 | Doi | 10.1113/jphysiol.2013.254474 |
| Citation | Hashimotodani Y, et al. (2013) Acute inhibition of diacylglycerol lipase blocks endocannabinoid-mediated retrograde signalling: evidence for on-demand biosynthesis of 2-arachidonoylglycerol. J Physiol 591(Pt 19):4765-76 |
| abstractText | The endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG) produced by diacylglycerol lipase alpha (DGLalpha) is one of the best-characterized retrograde messengers at central synapses. It has been thought that 2-AG is produced 'on demand' upon activation of postsynaptic neurons. However, recent studies propose that 2-AG is pre-synthesized by DGLalpha and stored in neurons, and that 2-AG is released from such 'pre-formed pools' without the participation of DGLalpha. To address whether the 2-AG source for retrograde signalling is the on-demand biosynthesis by DGLalpha or the mobilization from pre-formed pools, we examined the effects of acute pharmacological inhibition of DGL by a novel potent DGL inhibitor, OMDM-188, on retrograde eCB signalling triggered by Ca(2+) elevation, Gq/11 protein-coupled receptor activation or synergy of these two stimuli in postsynaptic neurons. We found that pretreatment for 1 h with OMDM-188 effectively blocked depolarization-induced suppression of inhibition (DSI), a purely Ca(2+)-dependent form of eCB signalling, in slices from the hippocampus, striatum and cerebellum. We also found that at parallel fibre-Purkinje cell synapses in the cerebellum OMDM-188 abolished synaptically induced retrograde eCB signalling, which is known to be caused by the synergy of postsynaptic Ca(2+) elevation and group I metabotropic glutamate receptor (I-mGluR) activation. Moreover, brief OMDM-188 treatments for several minutes were sufficient to suppress both DSI and the I-mGluR-induced retrograde eCB signalling in cultured hippocampal neurons. These results are consistent with the hypothesis that 2-AG for synaptic retrograde signalling is supplied as a result of on-demand biosynthesis by DGLalpha rather than mobilization from presumptive pre-formed pools. |
