Endocannabinoid signalling triggered by NMDA receptor-mediated calcium entry into rat hippocampal neurons.
Endocannabinoids are released from neurons in activity-dependent manners, act retrogradely on presynaptic CB(1) cannabinoid receptors, and induce short-term or long-term suppression of transmitter release. The endocannabinoid release is triggered by postsynaptic activation of voltage-gated Ca(2+) channels and/or G(q)-coupled receptors such as group I metabotropic glutamate receptors (I-mGluRs) and M(1)/M(3) muscarinic receptors. However, the roles of NMDA receptors, which provide another pathway for Ca(2+) entry into neurons, in endocannabinoid signalling have been poorly understood. In the present study, we investigated the possible contribution of NMDA receptors in endocannabinoid production by recording IPSCs in cultured hippocampal neurons. Under the conditions minimizing the activation of voltage-gated Ca(2+) channels, local application of NMDA (200 microm) transiently suppressed cannabinoid-sensitive IPSCs, but not cannabinoid-insensitive IPSCs. This NMDA-induced suppression was abolished by blocking NMDA receptors, CB(1) receptors and diacylglycerol lipase, but not by inhibiting voltage-gated Ca(2+) channels. When the postsynaptic neuron was dialysed with 30 mm BAPTA, the NMDA-induced suppression was reduced significantly. A lower dose of NMDA (20 microm) exerted little effect when applied alone, but markedly enhanced the cannabinoid-dependent suppression driven by muscarinic receptors or I-mGluRs. These data clearly indicate that the activation of NMDA receptors facilitates the endocannabinoid release either alone or in concert with the G(q)-coupled receptors.
Ohno-Shosaku
Takako
T
Department of Cellular Neuroscience, Graduate School of Medicine, Osaka University, Suita 565-0871, Japan.
Hashimotodani
Yuki
Y
Ano
Masato
M
Takeda
Sachi
S
Tsubokawa
Hiroshi
H
Kano
Masanobu
M
D000818:Animals; D000831:Animals, Newborn; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D063388:Endocannabinoids; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D053444:Inhibitory Postsynaptic Potentials; D008071:Lipoprotein Lipase / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D018721:Muscarinic Agonists / Q000494:pharmacology; D016202:N-Methylaspartate / Q000378:metabolism* / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010095:Oxotremorine / Q000031:analogs & derivatives / Q000494:pharmacology; D054799:Phospholipase C beta / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*; D012118:Resorcinols / Q000494:pharmacology
D015220:Calcium Channels; D063385:Cannabinoid Receptor Modulators; D002614:Chelating Agents; D063388:Endocannabinoids; D018690:Excitatory Amino Acid Agonists; D009025:Morpholines; D018721:Muscarinic Agonists; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D018094:Receptors, Metabotropic Glutamate; D011976:Receptors, Muscarinic; D016194:Receptors, N-Methyl-D-Aspartate; D012118:Resorcinols; D004533:Egtazic Acid; D010095:Oxotremorine; C079215:3,5-dihydroxyphenylglycine; D016202:N-Methylaspartate; C042743:oxotremorine M; D008071:Lipoprotein Lipase; D054799:Phospholipase C beta; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; C109925:AM 281; D005998:Glycine