Glial calcium.

This review summarizes current knowledge relating intracellular calcium and glial function. During steady state, glia maintain a low cytosolic calcium level by pumping calcium into intracellular stores and by extruding calcium across the plasma membrane. Glial Ca2+ increases in response to a variety of physiological stimuli. Some stimuli open membrane calcium channels, others release calcium from intracellular stores, and some do both. The temporal and spatial complexity of glial cytosolic calcium changes suggest that these responses may form the basis of an intracellular or intercellular signaling system. Cytosolic calcium rises effect changes in glial structure and function through protein kinases, phospholipases, and direct interaction with lipid and protein constituents. Ultimately, calcium signaling influence glial gene expression, development, metabolism, and regulation of the extracellular milieu. Disturbances in glial calcium homeostasis may have a role in certain pathological conditions. The discovery of complex calcium-based glial signaling systems, capable of sensing and influencing neural activity, suggest a more integrated neuro-glial model of information processing in the central nervous system.

Calcium excitability and oscillations in suprachiasmatic nucleus neurons and glia in vitro.

Converging lines of evidence suggest that the hypothalamic suprachiasmatic nucleus (SCN) is the site of the endogenous biological clock controlling mammalian circadian rhythms. To study the calcium responses of the cellular components that make up the clock, computer-controlled digital video and confocal scanning laser microscopy were used with the Ca2+ indicator dye fluo-3 to examine dispersed SCN cells and SCN explants with repeated sampling over time. Ca2+ plays an important second messenger role in a wide variety of cellular mechanisms from gene regulation to electrical activity and neurotransmitter release, and may play a role in clock function and entrainment. SCN neurons and astrocytes showed an intracellular Ca2+ increase in response to glutamate and 5-HT, two major neurotransmitters in afferents to the SCN. Astrocytes showed a marked heterogeneity in their response to the serial perfusion of different transmitters; some responded to both 5-HT and glutamate, some to neither, and others to only one or the other. Under constant conditions, most neurons showed irregular temporal patterns of Ca2+ transients. Expression of regular neuronal oscillations could be blocked by the inhibitory transmitter GABA. Astrocytes, on the other hand, showed very regular rhythms of cytoplasmic Ca2+ concentrations with periods ranging from 7 to 20 sec. This periodic oscillation could be initiated by in vitro application of glutamate, the putative neurotransmitter conveying visual input to the SCN critical for clock entrainment. Long-distance communication between glial cells, seen as waves of fluorescence moving from cell to cell, probably through gap junctions, was induced by glutamate, 5-HT, and ATP. These waves increased the period length of cellular Ca2+ rises to 45-70 sec. Spontaneously oscillating cells were common in culture medium, serum, or rat cerebrospinal fluid, but rare in HEPES buffer. One source for cytoplasmic Ca2+ increases was an influx of extracellular Ca2+, as seen under depolarizing conditions in about 75% of the astroglia studied. All neurotransmitter-induced Ca2+ fluxes were not dependent on voltage changes, as Ca2+ oscillations could be initiated under both normal and depolarizing conditions. Since neurotransmitters could induce a Ca2+ rise in the absence of extracellular Ca2+, the mechanisms of ultradian oscillations appear to depend on cycles of intracellular Ca2+ fluxes from Ca(2+)-sequestering organelles into the cytoplasm, followed by a subsequent Ca2+ reduction. In the adult SCN, fewer astrocytes are found than neurons, yet astrocytes frequently surround glutamate-immunoreactive axons in synaptic contact with SCN dendrites, isolating neurons from each other while maintaining contact with other astrocytes by gap junctions.(ABSTRACT TRUNCATED AT 400 WORDS)

Endothelin induces a sustained rise in intracellular calcium in hippocampal astrocytes.

We report that the endothelins, a newly described family of vasoactive peptides, have a profound effect on intracellular calcium levels of cultured rat hippocampal astrocytes that resembles the effect of endothelin (ET) on vascular smooth muscle cells (VSMCs) in many respects. The astrocyte's response has two components that can be distinguished by their extracellular calcium requirement and time course. Within seconds of application, ET induces a transient calcium spike that corresponds to a release of calcium from internal stores. The second component follows immediately, is dependent upon extracellular calcium, and maintains an elevated intracellular calcium level for many minutes. Sustained elevations of intracellular calcium can dramatically alter astrocyte morphology and induce cell division in many other cell types. ET may serve these functions, and thus form a communication link between blood vessels and neurons through astrocytes.

Ca2+ waves in astrocytes.

The glial cell is the most numerous cell type in the central nervous system and is believed to play an important role in guiding brain development and in supporting adult brain function. One type of glial cell, the astrocyte also may be an integral computational element in the brain since it undergoes neurotransmitter-triggered signalling. Here we review the role of the astrocyte in the central nervous system, emphasizing receptor-mediated Ca2+ physiology. One focus is the recent discovery that the neurotransmitter glutamate induces a variety of intracellular Ca2+ changes in astrocytes. Simple Ca2+ spikes or intracellular Ca2+ oscillations often appear spatially uniform. However, in many instances, the Ca2+ rise has a significant spatial dimension, beginning in one part of the cell it spreads through the rest of the cell in the form of a wave. With high enough agonist concentration an astrocyte syncitium supports intercellular waves which propagate from cell to cell over relatively long distances. We present results of experiments using more specific pharmacological glutamate receptor agonists. In addition to describing the intercellular Ca2+ wave we present evidence for another form of intercellular signalling. Some possible functions of a long-range glial signalling system are also discussed.

Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling.

The finding that astrocytes possess glutamate-sensitive ion channels hinted at a previously unrecognized signaling role for these cells. Now it is reported that cultured hippocampal astrocytes can respond to glutamate with a prompt and oscillatory elevation of cytoplasmic free calcium, visible through use of the fluorescent calcium indicator fluo-3. Two types of glutamate receptor--one preferring quisqualate and releasing calcium from intracellular stores and the other preferring kainate and promoting surface-membrane calcium influx--appear to be involved. Moreover, glutamate-induced increases in cytoplasmic free calcium frequently propagate as waves within the cytoplasm of individual astrocytes and between adjacent astrocytes in confluent cultures. These propagating waves of calcium suggest that networks of astrocytes may constitute a long-range signaling system within the brain.