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

Abstract

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 M),. Inhibition mediated by L-CCG-I had longlasting effects (Ͼ45 min) in ϳ30% of the SCN astrocytes tested. The inhibition could be mimicked by the L-type calcium channel blocker nimodipine (1 M) as well as by protein kinase C (PKC) activators phorbol 12,13-dibutyrate (10 M) and phorbol 12-myristate 13-acetate (500 nM), and blocked by the PKC inactivator (Ϯ)-1-(5-isoquinolinesulfonyl)-2-methylpiperazine (200 M), 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.

Neurobiological mechanisms for the regulation of mammalian sleep–wake behavior: Reinterpretation of historical evidence and inclusion of contemporary cellular and molecular evidence

“…Recent pharmacological and physiological studies have also shown that the activation of PPT kainate-type Glut receptors induces REM sleep (Datta, 2002;. It is also well known that the activation of kainate receptors increases the cytoplasmic free calcium concentration (Bernard et al, 1999;Bleakman and Lodge, 1998;Haak et al, 1997;Kovacs et al, 2000;Michaelis, 1998). In neurons, calcium ions can stimulate the production of cAMP and the activation of PKA via the activation AC (Cali et al, 1994;Ginty et al, 1991;Waltereit et al, 2001;Xia et al, 1996).…”

Reductions in N‐acetylaspartylglutamate and the 67 kDa form of glutamic acid decarboxylase immunoreactivities in the visual system of albino and pigmented rats after optic nerve transections

“…NAAG also has been found to be neuroprotective when the enzyme that degrades it in vivo is inhibited (Bruno et al, 1998a;Lu et al, 2000;Thomas et al, 2000). Extracellular NAAG can also act at metabotropic glutamate receptors on astrocytes (Haak et al, 1997;Wroblewska et al, 1998), resulting in the release of neuroprotective molecules, including transforming growth factor-␤ (Bruno et al, 1998b). It is evident from such findings that NAAG application does not always mimic the actions of glutamate, suggesting that its hydrolysis to glutamate is not a satisfactory explanation for the mechanisms of action of NAAG in the nervous system.…”

Cellular and chemical neuroscience of mammalian sleep

“…It is well known that activation of kainate receptors increases cytoplasmic free calcium concentration [136-140]. In neurons, calcium ions can stimulate the production of cyclic adenosine monophosphate (cAMP) and the activation of protein kinase A (PKA) via the activation of adenylyl cyclase (AC) [141-144].…”