CaィイD12+ィエD1-related abnormality in neuronal nicotinic acetylcholine receptor-mutant mice

神经元烟碱乙酰胆碱受体突变小鼠的CaiD12+CaiD1相关异常

• 批准号: 09044276
• 负责人: KIMURA Ikuko
• 金额: $ 4.8万
• 依托单位: Toyama Medical and Pharmaceutical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for international Scientific Research
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09044276/
• 关键词: nicotine; β2-knock out mouse; substantia nigra pars compacta; α7-subunit; methyllycaconitine; neuronal type-nicotinic acetylcholine receptor; dopaminergic neuron; receptor activity-modulating intracellular calcium; β2ノックアウトマウス; 中脳黒質; methyllycac

Desensitizing interaction between muscle (M)-and neuronal (N)-types of nicotinic acetylcholine receptors (nAChR) occurs through menthyllycaconitine (MLA)-sensitive slow CaィイD12+ィエD1 mobilization (RAMIC : receptor activity-modulating intracellular calcium) in neuromuscular synapse. To elucidate functional roles of N-nAChR in brain and identify the N-nAChR subunit regulating M-nAChR in neuromuscular synapse, we assessed the intracellular CaィイD12+ィエD1 level by imaging fura-2-loaded cells in brain slices (substantia nigra pars compacta) and in single skeletal muscle cells (flexor digitorum brevis) of mice lacking the nAChRβ2-subunit. 1. Neuromuscular synapse : Either RAMIC induced by cytisine (20μM) and Ach (3μM) or desensitization in opening frequency of ACh-activated channel current was observed β2-mutant (-/-) mice in the same manner as in β2(+/+) wildtype sibling mice. 2. Substantia nigra pars compacta : Superfusion with nicotine (10-100μM) caused a long-lasting rise of intracellular CaィイD12+ィエD1 level in an extracellular CaィイD12+ィエD1-dependent manner in wild-type mice but not in β2(-/-) mutant mice. Alpha 7-subunit-selective agonist choline (10mM) caused a MLA-sensitive increase of intracellular CaィイD12+ィエD1 level both in wild-type and β2(-/-) mutant mice. In nigral dopaminergic neurons, nicotine can elicit CaィイD12+ィエD1 mobilization via two distinct mechanisms of either activation of β2- or of α7-subunit-containing nAChR. In neuromuscular synapse, β2-subunit is less involved to produce a MLA-sensitive RAMIC. I

肌肉 (M) 型和神经元 (N) 型烟碱乙酰胆碱受体 (nAChR) 之间的脱敏相互作用是通过神经肌肉突触中薄荷基卡乌头碱 (MLA) 诱导的缓慢 CaD12+D1 动员（RAMIC：受体活性调节细胞内钙）发生的。阐明 N-nAChR 在大脑中的功能作用并鉴定 N-nAChR 亚基为了调节神经肌肉突触中的 M-nAChR，我们通过对缺乏 nAChRβ2- 的小鼠脑切片（黑质致密部）和单个骨骼肌细胞（趾短屈肌）中加载 fura-2 的细胞进行成像来评估细胞内 CaD12+D1 水平1. 神经肌肉突触：由金雀花碱 (20μM) 诱导的 RAMIC。以与β2(+/+)野生型同胞小鼠相同的方式观察β2-突变型(-/-)小鼠中的Ach(3μM)或ACh激活通道电流的开放频率脱敏。 2.黑质致密部：灌输尼古丁 (10-100μM) 导致细胞外细胞内 CaD12+D1 水平持久升高野生型小鼠中的 CaD12+D1 依赖性方式，但 β2(-/-) 突变小鼠中则不然。Alpha 7 亚基选择性激动剂胆碱 (10mM) 导致野生型小鼠细胞内 CaD12+D1 水平的 MLA 敏感性增加。和 β2(-/-) 突变小鼠的黑质多巴胺能神经元中，尼古丁可以诱发。 CaiD12+D1 通过激活包含 β2 或 α7 亚基的 nAChR 的两种不同机制进行动员。在神经肌肉突触中，β2 亚基较少参与产生 MLA 敏感的 RAMIC I。

项目成果

Kimura I, Tsuneki H, Dezaki K, Nojima H: "Desensitizing function of calcium mobilized by the postsynaptic neuronal-type nicotinic acetylcholine receptors at the neuromuscular junction"Yakugaku Zasshi. 19. 1-15 (1999)

Kimura I、Tsuneki H、Dezaki K、Nojima H：“神经肌肉接头处突触后神经元型烟碱乙酰胆碱受体动员钙的脱敏功能”Yakugaku Zasshi。

Tsuneki H, Lena C, Korn H Changeux J-P: "Calcium mobilization elicited by two types of nicotinic acetylcholine receptors in mouse substantia nigra pars comacta"Eur J Neurosci. (in press). (2000)

Tsuneki H、Lena C、Korn H Changeux J-P：“小鼠黑质小丘部中两种类型的烟碱乙酰胆碱受体引起的钙动员”Eur J Neurosci。

Kimura I: "Calcium-dependent desensitizing function of the postsynaptic neuronal-type nicotinic acetylcholine receptors at the neuromuscular junction"Pharmacology and Therapeutics. 77. 183-202 (1998)

Kimura I：“神经肌肉接头处突触后神经元型烟碱乙酰胆碱受体的钙依赖性脱敏功能”药理学和治疗学。

Salim SY,Dezaki K,Tsuneki H,Abdel-Zaher AO,Kimura I: "Calcitonin fene-related peptide potentiates nicotinic acetylcholine receptor-operated slow Ca^<2+> mobilization at mouse muscle endplates" British Journal of Pharmacology. 125. 277-282 (1998)

Salim SY、Dezaki K、Tsuneki H、Abdel-Zaher AO、Kimura I：“降钙素芬相关肽增强烟碱乙酰胆碱受体操作的小鼠肌肉终板的缓慢 Ca^2 动员”英国药理学杂志。

Nojima H, Sasaki T, Kimura I: "Arachidonic acid and orostaglandin D_2 cooperatively accelerate desensitization of nicotinic acetylcholine receptor channel in mouse skeletal muscles"Brain Research. 852. 233-238 (2000)

Nojima H、Sasaki T、Kimura I：“花生四烯酸和口腔前列腺素 D_2 协同加速小鼠骨骼肌中烟碱乙酰胆碱受体通道的脱敏”脑研究。