Sunday, April 28, 2024
4/28/2024
¿ DESCRIPTION (provided by applicant): Astrocytes interact with all types of neural cells by establishing direct cell-cell contacts through gap junctions and/or by releasing gliotransmitters which modulate synaptic activity, brain microcirculation, as well as neuroinflammatory and metabolic responses. Among the various types of paracrine signals, purinergic ATP-mediated signaling is emerging as the most prominent mechanism by which astrocytes interact among themselves and with neurons. This is because neural cells release and respond to ATP. ATP release from cells occurs through distinct mechanisms including ion channels. Recently, Pannexin1 (Panx1), a vertebrate ortholog of invertebrate gap junction protein, was found to form channels that we and others have proposed to be the site for ATP release. Pannexins are abundantly expressed in the CNS, both in glia and neurons, where they have been implicated in ischemic neuronal death and epileptiform activity. In concordance with the proposed role of Panx1 channels in hyperactivity, we recently found, using two different mouse lines with global Panx1 deletion that ATP release through these channels contributes to prolong the clinical manifestations of status epilepticus. A main question that remains to be answered, however, regards the cell type (astrocyte or neuron) that contributes to Panx1-mediated seizures. Thus, the overall aim of this grant application is to determine key missing information regarding cell-cell communication via Pannexin1 channels in the CNS, including the biophysical properties of these channels and the signal transduction events both leading to and resulting from Panx1 activation. For that we will use newly available conditional Panx1-null mice to directly evaluate the extent to which astrocyte or neuronal Panx1 channels contribute to status epilepticus by releasing ATP and to provide new mechanistic understanding of gating and signal transduction events of this new type of channel.
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