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The Journal of Neuroscience, November 26, 2003, 23(34):10944-10952

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Cellular/Molecular
Dual Regulation of Calcium Oscillation in Astrocytes by Growth Factors and Pro-Inflammatory Cytokines via the Mitogen-Activated Protein Kinase Cascade

Mitsuhiro Morita,¹ Chitose Higuchi,¹ Takanori Moto,¹ Nagisa Kozuka,¹ Jinichi Susuki,¹ Rurika Itofusa,¹ Jiro Yamashita,² and Yoshihisa Kudo¹

¹Laboratory of Cellular Neurobiology, School of Life Science, Tokyo University of Pharmacy and Life Science, 192-0392 Tokyo, Japan, and ²Department of Neurophysiology, University of Tokyo, Graduate School of Medicine, 113-0033 Tokyo, Japan

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-1 or tumor necrosis factor-), 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.

Key words: astrocyte; calcium oscillation; epidermal growth factor; basic fibroblast growth factor; lipopolysaccharide; interleukin-1; tumor necrosis factor-; mitogen-activated protein kinase; metabotropic glutamate receptor; inositol-1,4,5 triphosphate

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Received June 12, 2003; revised September 11, 2003; accepted October 2, 2003.

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