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Cyclic nucleotide-gated (CNG) channels are nonselective cation channels activated by cyclic AMP (cAMP) or cyclic GMP (cGMP). They were originally identified in retinal and olfactory receptors, but evidence has also emerged for their expression in several mammalian brain areas. Because cGMP and cAMP control important aspects of glial cell physiology, we wondered whether CNG channels are expressed in astrocytes, the most functionally relevant glial cells in the CNS. Immunoblot and immunofluorescence experiments demonstrated expression of the CNG channel olfactory-type A subunit, CNGA2, in cultured rat cortical astrocytes. In patch-clamp experiments, currents elicited in these cells by voltage ramps from -100 to +100 mV in the presence of the cGMP analogue, dB-cGMP, were significantly reduced by the CNG channel blockers, L-cis-diltiazem (LCD) and Cd(2+) . The reversal potentials of the LCD- and Cd(2+) -sensitive currents were more positive than that of K(+) , as expected for a mixed cation current. Noninactivating, voltage-independent currents were also elicited by extracellular application of the membrane permeant cGMP analogue, 8-Br-cGMP. These effects were blocked by LCD and were mimicked by natriuretic peptide receptor activation and inhibition of phosphodiesterase activity. Voltage-independent, LCD-sensitive currents were also elicited by 8-Br-cGMP in astrocytes of hippocampal and neocortical brain slices. Immunohistochemistry confirmed a broad distribution of CNG channels in astrocytes of the rat forebrain, midbrain, and hindbrain. These findings suggest that CNG channels are downstream targets of cyclic nucleotides in astrocytes, and they may be involved in the glial-mediated regulation of CNS functions under physiological and pathological conditions., (Copyright © 2012 Wiley Periodicals, Inc.)

Though accumulating evidence shows that the metabotropic glutamate receptor 5 (mGluR5) mediates some of the actions of extracellular glutamate after cocaine use, the cellular events underlying this action are poorly understood. In this review, we will discuss recent results showing that mGluR5 receptors are key regulators of astrocyte activity. Synaptic release of glutamate activates mGluR5 expressed in perisynaptic astrocytes and generates intense Ca2+ signaling in these cells. Ca2+ oscillations, in turn, trigger the release from astrocytes of the gliotransmitter glutamate, which modulates neuronal excitability by activating NMDA receptors. By integrating these results with the most recent evidence demonstrating the importance of astrocytes in the regulation of neuronal excitability, we propose that astrocytes are involved in mediating some of the mGluR5-dependent drug-induced behaviors.

Glutamatergic and purinergic signalling play key roles in synaptic transmission and modulation in the CNS. Here, we review recent evidence showing that glial cells, and in particular astrocytes, are active players in ATP and glutamate signalling in the brain. ATP and glutamate coordinately activate astrocytes, through the mobilization of their internal Ca2+, which in turn triggers the release from astrocytes of several neuroactive molecules including ATP and glutamate themselves. These 'gliotransmitters' signal either to astrocytes, where they generate Ca2+ waves, or to neurons, where they modulate synaptic transmission and neuronal excitability. By using microfabricated lanes of adhesive substrate, we provide further evidence for a diffusible factor-mediated propagation of Ca2+ waves and, through flash photolysis experiments in hippocampal slices, we show that glutamate and ATP cooperate in the generation of the astrocytic Ca2+ signal. Once astrocytes are activated they provide both excitatory and inhibitory effects on neighbouring neurons. Through the Ca2+-dependent release of glutamate, which acts on extrasynaptic neuronal NMDA receptors, astrocytes excite neurons while, in contrast, ATP released from astrocytes, after the delayed conversion to adenosine, causes neuronal suppression.

Changes in intracellular Ca2+ levels are an important signal underlying neuron-glia cross-talk, but little is known about the possible role of voltage-gated Ca2+ channels (VGCCs) in controlling glial cell Ca2+ influx. We investigated the pharmacological and biophysical features of VGCCs in cultured rat cortical astrocytes. In whole-cell patch-clamp experiments, L-channel blockade (5 microM nifedipine) reduced Ba2+ current amplitude by 28% of controls, and further decrease (32%) was produced by N-channel blockade (3 microM omega-conotoxin-GVIA). No significant additional changes were observed after P/Q channel blockade (3 microM omega-conotoxin-MVIIC). Residual current (36% of controls) amounted to roughly the same percentage (34%) that was abolished by R-channel blockade (100 nM SNX-482). Electrophysiological evidence of L-, N-, and R-channels was associated with RT-PCR detection of mRNA transcripts for VGCC subunits alpha1C (L-type), alpha1B (N-type), and alpha1E (R-type). In cell-attached recordings, single-channel properties (L-currents: amplitude, -1.21 +/- 0.02 pA at 10 mV; slope conductance, 22.0 +/- 1.1 pS; mean open time, 5.95 +/- 0.24 ms; N-currents: amplitude, -1.09 +/- 0.02 pA at 10 mV; slope conductance, 18.0 +/- 1.1 pS; mean open time, 1.14 +/- 0.02 ms; R-currents: amplitude, -0.81 +/- 0.01 pA at 20 mV; slope conductance, 10.5 +/- 0.3 pS; mean open time, 0.88 +/- 0.02 ms) resembled those of corresponding VGCCs in neurons. These novel findings indicate that VGCC expression by cortical astrocytes may be more varied than previously thought, suggesting that these channels may indeed play substantial roles in the regulation of astrocyte Ca2+ influx, which influences neuron-glia cross-talk and numerous other calcium-mediated glial-cell functions., (Copyright 2003 Wiley-Liss, Inc.)