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.

Public Health Relevance

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 release of ATP does not require cell damage and occurs through multiple mechanisms, including ion channels. We recently found that Pannexin1 (Panx1) channels mediate the release of ATP that prolongs status epilepticus. A major question that remains to be answered, however, regards whether astrocytes or neurons are the cells that contribute to Panx1-mediated seizures. Thus, the goals of this project are to determine the extent to which astrocyte and neuronal Panx1 contribute to status epilepticus by releasing ATP and to characterize the biophysical properties and signal transduction events mediating pannexin1 channel activation in solitary astrocytes and cultured neurons. These studies are expected to provide new insights for therapeutic intervention in diseases involving the activation of Pannexin1 channels, such as has been reported to occur in seizures

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS092786-05
Application #
9664003
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Leenders, Miriam
Project Start
2017-11-11
Project End
2021-01-31
Budget Start
2019-04-01
Budget End
2021-01-31
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
New York Medical College
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
041907486
City
Valhalla
State
NY
Country
United States
Zip Code
10595
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