α1-Adrenergic Modulation of Metabotropic Glutamate Receptor-induced Calcium Oscillations and Glutamate Release in Astrocytes

Abstract

Astrocytic responses to activation of metabotropic glutamate receptors group I (mGluRs I) and ␣ 1 -adrenoreceptors in cultured cells have been assessed using spectral analyzes and calcium imaging. Concentrationdependent changes were observed after stimulation with the mGluR I agonist (S)-3,5-dihydroxyphenylglycine (DHPG). These responses changed from a regular low frequency signal with sharp peaks at 1 M to a pronounced stage of irregularity at 10 M. After stimulation with 100 M the signal was again homogenous in shape and regularity but occurred at a higher frequency. In contrast, the spectral properties after stimulation with the ␣ 1 -adrenoreceptor agonist phenylephrine, exhibited considerable variation for all investigated concentrations. DHPG-induced increases in [Ca 2؉ ] i were also associated with astroglial glutamate release, whereas no release was observed after noradrenergic stimulation. Both DHPG-mediated calcium signaling and glutamate release were inhibited by preincubation with 10 or 100 M phenylephrine. Collectively, the present investigation provides new information about the spatialtemporal characteristics of astroglial intracellular calcium responses and demonstrates distinct differences between noradrenergic and glutamatergic receptors regarding intracellular calcium signaling and coupling to glutamate release. The noradrenergic modulation of DHPG-induced responses indicates that intracellular astroglial processes can be regulated in a bi-directional feedback loop between closely connected astrocytes and neurons in the central nervous system. Astrocytes, the main population of glial cells, form gap junction-coupled multicellular networks and communicate among themselves through variations in intracellular calcium concentration ([Ca 2ϩ ] i ) 1 (1). These cells express a calcium-based excitability in which receptor-mediated calcium elevations can propagate as intracellular waves over considerable distances (1, 2). A diverse range of [Ca 2ϩ ] i changes are induced in astrocytes after exposure to various neurotransmitters (2-6) and the cells display [Ca 2ϩ ] i oscillations and intracellular waves in response to neuronal activity (7-9). Previous results demonstrate the importance of glutamate for the mediation of these neuronal-glial interactions. However, the potential contribution of other important neurotransmitters such as those belonging to the noradrenergic system has not yet been fully investigated.Variations in astrocytic [Ca 2ϩ ] i mediate the uptake and release of different neuroactive substances (10) such as arachidonic acid, neurotrophins, and neurotransmitters, and via this mechanism possibly modulate synaptic transmission (11-13). Consistent with this, previous studies have shown that activation of glial metabotropic glutamate receptors in concert with ␤-adrenoreceptors (␤-AdRs) can result in depression of synaptic activity in which the release of cAMP from astrocytes is central (14). Furthermore, adrenergic and glutamatergic interactions can also greatly affect both cAMP-and ...

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