Mode of action and physiological significance of endogenous cannabinoids as a retrograde messenger at central synapses

内源性大麻素作为中央突触逆行信使的作用模式和生理意义

• 批准号: 13854028
• 负责人: KANO Masanobu
• 金额: $ 66.89万
• 依托单位: Kanazawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (S)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13854028/
• 关键词: retrograde signal; cannabinoid; synaptic transmission; cerebellum; hippocampus; calcium; CB1 receptor; Gq-coupled receptor; シナプス伝達調節; 大脳基底核; フォスフォリパーゼCβ; 代謝型グルタミン酸受容体

The active component of marijuana (Δ^9-tetrahydrocannabinol) exerts various psychomotor actions through binding to the CB1 cannabinoid receptor that is distributed widely in the central nervous system. Two candidates for endogenous cannabinoid (eCB) (i.e.,endogenous ligands for the CB1 receptor) are anandamide and 2-arachidonoylglycerol. The CB1 receptor is present at presynaptic sites of central neurons and the binding of cannabinoids to this receptor results in reduction of neurotransmitter release from presynaptic terminals. However, at the beginning of the present research project, it was largely unknown what stimuli to neurons could produce eCBs and what roles eCBs played in brain functions. We have examined roles of eCBs in modulation of synaptic transmission by using electrophysiological methods and have obtained the following results.In hippocampal neurons and cerebellar Purkinje cells, depolarization and resultant elevation of intracellular Ca^<2+> concentration causes production of eCBs that retrogradely activates presynapric CB1 receptors and induces transient suppression of neurotransmitter release. Activation of Gq-coupled receptors including group I metabotropic glutamate receptors and M_1/M_3 muscarinic acetylcholine receptors also induces eCB-mediated rretrograde suppression of neurotransmitter release. Furthermore, we have found that, in cutured hippocampal neurons, weak depolarization and mild activation of M_1/M_3 muscarinic acetylcholine receptors effectively induce eCB-mediated retrograde suppression, whereas either stimulus alone causes no detectable suppression. We have disclosed that this synergism is attributable to the property of phospholipase Css1 (PLCss1) that is activated by a subunit of Gq/11 and also sensitive to physiological range of intracellular Ca^<2+>. Therefore, PLCss1 can function as a coincidence detector of cholinergic afferent activity (i.e.,presynaptic activity) and postsynaptic depolarization.

大麻的活性成分（Δ ^9-四氢大麻酚）通过与广泛分布在中枢神经系统中的CB1大麻素受体结合而发挥各种精神作用。内源性大麻素（eCB）的两种候选物（即，CB 1受体的内源性配体）是花生四烯酸和2-花生四烯酸甘油。CB1受体存在于中枢神经元的突触前部位，大麻素与该受体的结合导致突触前末梢释放的神经递质减少。然而，在本研究项目开始时，很大程度上不知道对神经元的什么刺激可以产生eCBs以及eCBs在大脑功能中扮演什么角色。我们用电生理学方法研究了eCB在调节突触传递中的作用，并获得了以下结果：在海马神经元和小脑浦肯野细胞中，去极化和由此引起的细胞内Ca ^2+浓度升高导致eCB的产生，后者逆行激活突触前CB 1受体，并诱导神经递质释放的短暂抑制。Gq偶联受体（包括I型代谢型谷氨酸受体和M_1/M_3型毒蕈碱型乙酰胆碱受体）的激活也诱导eCB介导的神经递质释放的逆行抑制。此外，我们还发现，在培养的海马神经元中，弱的去极化和M_1/M_3毒蕈碱乙酰胆碱受体的轻度激活可有效地诱导eCB介导的逆行抑制，而单独的刺激均不引起可检测到的抑制。我们已经发现这种协同作用归因于磷脂酶Css 1（PLCss 1）的特性，该特性被Gq/11的亚基激活，并且对细胞内Ca ^2+的生理范围敏感。因此，PLC β 1可以作为胆碱能传入活动的符合检测器（即，突触前活动）和突触后去极化。

项目成果

Fukudome, Y.: "Insulin-like growth factor-I as a promoting factor for cerebellar Purkinje cell development"Eur.J.Neurosci.. 17. 2006-2016 (2003)

Fukudome, Y.：“胰岛素样生长因子-I 作为小脑浦肯野细胞发育的促进因子”Eur.J.Neurosci.. 17. 2006-2016 (2003)

T. Ohno, Shosaku: "Cooperative endocannabinoid production by neuronal depolarization and group I metabotropic glutamate receptor activation"Eur. J. Neurosci.. (in press). (2002)

T. Ohno, Shosaku：“神经元去极化和 I 类代谢型谷氨酸受体激活协同产生内源性大麻素”Eur。

ORP150/HSP12A regulates Purkinje cell survival : A role for ER stress in cerebellar development.

ORP150/HSP12A 调节浦肯野细胞存活：内质网应激在小脑发育中的作用。

• 发表时间: 2004
• 期刊: J.Neurosci. 24
• 作者: Kitao;Y.
• 通讯作者: Y.

mGluR1 in cerebellar Purkinje cells is required for normal association of temporally contiguous stimuli in classical conditioning

• DOI: 10.1046/j.1460-9568.2002.02407.x
• 发表时间: 2002-12-01
• 期刊: EUROPEAN JOURNAL OF NEUROSCIENCE
• 影响因子: 3.4
• 作者: Kishimoto, Y;Fujimichi, R;Kirino, Y
• 通讯作者: Kirino, Y

狩野方伸: "内因性カンナビノイドによる逆行性シナプス伝達 学術月報"日本学術振興会. 5 (2003)

Masanobu Kano：“内源性大麻素的逆行突触传递。科学月报”日本科学促进会 5 (2003)。