星形胶质细胞的选择性调控

tissue injury and improves functional recovery suggesting that excessive purinergic signaling

contributes to secondary damage following spinal cord injury 24.

NIH-PA Author Manuscript

NIH-PA Author Manuscript

NIH-PA Author ManuscriptMechanisms of ATP releasePurinergic signaling represents the most important pathway by which astrocytes communicatewith other cells in CNS. A key step to understand the modulation of astrocytic function istherefore to define the mechanism by which these electrically unexcitable cells release ATP.Several pathways of ATP release have been proposed, including channel-mediated release,exocytosis of ATP containing vesicles, connexin (C×) hemichannels, and P2×7 receptorhemichannels, possibly linked to pannexins (reviewed in 25. Several observations indicate thatC×-hemichannels are the most significant mechanism of ATP release from astrocytes. It hasbeen shown that: C×-deficient glia cell lines increased ATP release 3 to 10-fold aftertransfection with C×43 22; C×-channel blockers (NPPB and FFA) potently inhibited ATPrelease 26; and single channel recordings indicate that ATP can exit through C×43hemichannels 27. Cultured neurons do not release ATP in response to K+ or receptor activation,suggesting that release of ATP from synaptic vesicles is low 28. Although neurons express thegap junction protein, C×36 29., this connexin has a small single channel conductance and isimpermeable to larger molecules, including Lucifer yellow and ATP 30. Astrocytes can releasemany other transmitters, including PGE2, glutamate, TNF-α, and d-serine, which play a rolein paracrine signaling between astrocytes and neurons, endothelial cells, and microglial cells.The pathways for release of these gliotransmitters have not been established. Nevertheless,excessive release of gliotransmitters in the setting of ischemia is likely contributing toadditional cellular damage, similar to the observations of increased ATP release in spinal cordinury.Astrocytic Ca2+ signaling as an integral part of brain functionPurinergic signaling represents the primary pathway for astrocyte-astrocyte signaling.

Emerging evidence indicates that astrocytes also modulate the function of other cell types in

brain by release of ATP and other gliotransmitters including glutamate, PGE2, and d-serine.

Several methods by which astrocytes modulate brain function are described here:

Synaptic transmission—A flurry of studies has over the past few years documented that

astrocytes can modulate neuronal Ca2+ levels and synaptic transmission by means of Ca2+

signaling. For example, spontaneous astrocytic Ca2+ oscillations and subsequent glutamate

release can drive NMDA-receptor-mediated neuronal excitation in the rat ventrobasal thalamus31, and astrocytes can potentiate inhibitory transmission in the hippocampus through a pathway

that is sensitive to kainate-receptor antagonists 32. These and other studies have pointed to

glutamate and ATP/adenosine as key mediators of astrocyte-to-neuron signaling 33. Astrocytic

release of ATP leads to the production of adenosine in the extracellular space by the action of

highly expressed nucleotidases that degrade ATP with a rapid time constant (～200 ms) 34.

Adenosine then acts as is a potent neurotransmitter, with pervasive and generally inhibitory

effects on neuronal activity 34. Several recent lines of work have demonstrated that astrocytes

can control network activity in both cortex and hippocampus through adenosine resulting from

astrocytic ATP release 28, 35. Adenosine has both presynaptic and postsynaptic effects.

Presynaptically, adenosine A1 receptors inhibited Ca2+ channel opening resulting in reduced

transmitter release, whereas postsynaptically, A1 receptors opened K+ channels resulting in

hyperpolarization and decreased neuronal activity 34. In a resting state, low levels of

extracellular adenosine tonically dampened neural activity, and the A1 receptor antagonist,

DPCPX, increased spontaneous cortical activity. Conversely, adenosine or the A1 specific

agonist CCPA potently suppressed local activity 34. Interestingly, adenosine and ATP have

recently been implicated in the depression of synaptic activity associated with increased