Fig. 1.

Possible scenarios relating extracellular Ca²⁺ depletion to CX43-dependent release of ATP from astroglia. Activation of individual synapses could be sufficient to deplete extracellular Ca²⁺ in the local environment and thus trigger Cx43-dependent release of ATP from a local astroglial process (top). Otherwise, synchronous activity of multiple synapses could be required to trigger the spatially and temporally integrated depletion of extracellular Ca²⁺ to an extent sufficient to initiate ATP release from astrocytes on a global scale (middle). Alternatively, local Ca²⁺ depletion–triggered activation of Cx43 and release of ATP (bottom) could initiate a spreading, self-sustaining wave of Ca²⁺-dependent ATP release from astroglia. The underlying regenerative mechanism may involve Ca²⁺ store–generated long-range Ca²⁺ oscillations propagating inside individual astrocytes and across interastrocyte gap junctions or, alternatively, activation of purinergic “autoreceptors” in astroglia (24), or both.