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.
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
|Lauková, Marcela; Velíšková, Jana; Velíšek, Libor et al. (2018) Developmental and sex differences in tetramethylenedisulfotetramine (TMDT)-induced syndrome in rats. Dev Neurobiol 78:403-416|
|Velíšková, Jana; Silverman, Jill L; Benson, Melissa et al. (2018) Autistic traits in epilepsy models: Why, when and how? Epilepsy Res 144:62-70|
|Iacoba?, Dumitru A; Chachua, Tamar; Iacoba?, Sanda et al. (2018) ACTH and PMX53 recover synaptic transcriptome alterations in a rat model of infantile spasms. Sci Rep 8:5722|
|Clasadonte, Jerome; Scemes, Eliana; Wang, Zhongya et al. (2017) Connexin 43-Mediated Astroglial Metabolic Networks Contribute to the Regulation of the Sleep-Wake Cycle. Neuron 95:1365-1380.e5|
|Scemes, Eliana; Velíšková, Jana (2017) Exciting and not so exciting roles of pannexins. Neurosci Lett :|
|Hanstein, Regina; Hanani, Menachem; Scemes, Eliana et al. (2016) Glial pannexin1 contributes to tactile hypersensitivity in a mouse model of orofacial pain. Sci Rep 6:38266|