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Volume 17, Number 5, Issue of March 1, 1997 pp. 1825-1837
Copyright ©1997 Society for Neuroscience

Metabotropic Glutamate Receptor Activation Modulates Kainate and Serotonin Calcium Response in Astrocytes

Received Oct. 8, 1996; revised Dec. 12, 1996; accepted Dec. 16, 1996.

Laurel L. Haak¹, H. Craig Heller¹, and Anthony N. van den Pol²

¹ Department of Biological Sciences, Stanford University, Stanford, California 94305-5020, and ² Section of Neurosurgery, Yale University School of Medicine, New Haven, Connecticut 06520

Although metabotropic glutamate receptor (mGluR) modulation has been studied extensively in neurons, it has not been investigated in astrocytes. We studied modulation of glutamate-evoked calcium rises in primary astrocyte cultures using fura-2 ratiometric digital calcium imaging. Calcium plays a key role as a second messenger system in astrocytes, both in regulation of many subcellular processes and in long distance intercellular signaling. Suprachiasmatic nucleus (SCN) and cortical astrocytes showed striking differences in sensitivity to glutamate and to mGluR agonists, even after several weeks in culture. Kainate-evoked intracellular calcium rises were inhibited by concurrent application of the type I and II mGluR agonists quisqualate (10 µM), trans-(±)-1-amino-1,3-cyclopentanedicarboxylate (100-500 µM), and (2S-1S-2S)-2-(carboxycyclopropyl)glycine (L-CCG-I) (10 µM). Inhibition mediated by L-CCG-I had long-lasting effects (>45 min) in ~30% of the SCN astrocytes tested. The inhibition could be mimicked by the L-type calcium channel blocker nimodipine (1 µM) as well as by protein kinase C (PKC) activators phorbol 12,13-dibutyrate (10 µM) and phorbol 12-myristate 13-acetate (500 nM), and blocked by the PKC inactivator (±)-1-(5-isoquinolinesulfonyl)-2-methylpiperazine (200 µM), suggesting a mechanism involving PKC modulation of L-type calcium channels. In contrast, mGluRs modulated serotonin (5HT)-evoked calcium rises through a different mechanism. The type III mGluR agonist L-2-amino-4-phosphonobutyrate consistently inhibited 5HT-evoked calcium rises, whereas in a smaller number of cells quisqualate and L-CCG-I showed both inhibitory and additive effects. Unlike the mGluR-kainate interaction, which required a pretreatment with an mGluR agonist and was insensitive to pertussis toxin (PTx), the mGluR modulation of 5HT actions was rapid and was blocked by PTx. These data suggest that glutamate, acting at several metabotropic receptors expressed by astrocytes, could modulate glial activity evoked by neurotransmitters and thereby influence the ongoing modulation of neurons by astrocytes.

Key words: astrocytes; suprachiasmatic nucleus; calcium; serotonin; kainate; metabotropic glutamate receptors; ionotropic glutamate receptor; digital imaging; cortex

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