Morita Mitsuhiro, Higuchi Chitose, Moto Takanori, Kozuka Nagisa, Susuki Jinichi, Itofusa Rurika, Yamashita Jiro, Kudo Yoshihisa
Laboratory of Cellular Neurobiology, School of Life Science, Tokyo University of Pharmacy and Life Science, 192-0392 Tokyo, Japan.
J Neurosci. 2003 Nov 26;23(34):10944-52. doi: 10.1523/JNEUROSCI.23-34-10944.2003.
In response to neurotransmitters, astrocytes show various types of calcium increase (transient, oscillatory, and complex), the physiological significance of which is still controversial. To explore this variability, we examined factors affecting the calcium increase pattern in cultured astrocytes and investigated the consequences of the astrocytic calcium response in slice preparations. We found that growth factors (GFs) (EGF plus basic FGF) promoted calcium oscillation in response to glutamate, ATP, or thimerosal (which directly activates the inositol-1,4,5 triphosphate receptor) and that this effect was suppressed by pro-inflammatory cytokines (interleukin-1beta or tumor necrosis factor-alpha), lipopolysaccharide, or a MEK (mitogen-activated protein kinase kinase) inhibitor, suggesting dual regulation of calcium oscillation in astrocytes by factors affecting brain function and pathology via the mitogen-activated protein kinase (MAPK) cascade. The calcium oscillation was accompanied by enlargement of the calcium store, cell proliferation, and the development of a hypertrophic morphology. The cytokines suppressed GF-induced MAPK-dependent immediate early gene promoter activation, but not phosphorylation of extracellular signal-regulated kinase (ERK), showing that they affected gene regulation by acting on the MAPK cascade downstream of ERK. In slice preparations, a metabotropic glutamate receptor agonist converted the spontaneous neuronal calcium increase, attributable to synaptic transmission, to an oscillatory response similar to that seen in astrocytes in culture, indicating that the calcium response in astrocytes acted as a feedback mechanism on the activity of neighboring neurons. This is the first evidence for a dual regulation of calcium oscillation by physiological factors and for the control of calcium dynamics actually being used in physiological processes.
作为对神经递质的反应，星形胶质细胞会出现各种类型的钙增加（瞬态、振荡性和复合型），其生理意义仍存在争议。为了探究这种变异性，我们研究了影响培养的星形胶质细胞钙增加模式的因素，并调查了切片制备中星形胶质细胞钙反应的后果。我们发现生长因子（GFs）（表皮生长因子加碱性成纤维细胞生长因子）能促进对谷氨酸、三磷酸腺苷（ATP）或硫柳汞（直接激活肌醇-1,4,5-三磷酸受体）的钙振荡，且这种效应会被促炎细胞因子（白细胞介素-1β或肿瘤坏死因子-α）、脂多糖或丝裂原活化蛋白激酶激酶（MEK）抑制剂所抑制，这表明通过丝裂原活化蛋白激酶（MAPK）级联反应，影响脑功能和病理的因素对星形胶质细胞的钙振荡具有双重调节作用。钙振荡伴随着钙储存的扩大、细胞增殖以及肥大形态的发展。细胞因子抑制了生长因子诱导的MAPK依赖性即刻早期基因启动子激活，但不影响细胞外信号调节激酶（ERK）的磷酸化，表明它们通过作用于ERK下游的MAPK级联反应来影响基因调控。在切片制备中，一种代谢型谷氨酸受体激动剂将归因于突触传递的自发性神经元钙增加转变为类似于培养的星形胶质细胞中所见的振荡反应，这表明星形胶质细胞中的钙反应作为对相邻神经元活动的一种反馈机制。这是生理因素对钙振荡进行双重调节以及钙动力学控制实际用于生理过程的首个证据。
