Pannexin 1 channels and ATP release in epilepsy: two sides of the same coin: The contribution of pannexin-1, connexins,and CALHM ATP-release channels to purinergic signaling

Purinergic signaling mediated by ATP and its metabolites contributes to various brain physiological processes as well as to several pathological conditions, including neurodegenerative and neurological disorders, such as epilepsy. Among the different ATP release pathways, pannexin 1 channels represent one of the major conduits being primarily activated in pathological contexts. Investigations on in vitro and in vivo models of epileptiform activity and seizures in mice and human tissues revealed pannexin 1 involvement in aberrant network activity and epilepsy, and highlighted that pannexin 1 exerts a complex role. Pannexin 1 can indeed either sustain seizures through release of ATP that can directly activate purinergic receptors, or tune down epileptic activity via ATP-derived adenosine that decreases neuronal excitability. Interestingly, in-depth analysis of the literature unveils that this dichotomy is only apparent, as it depends on the model of seizure induction and the type of evoked epileptiform activity, two factors that can differentially activate pannexin 1 channels and trigger distinct intracellular signaling cascades. Here, we review the general properties and ATP permeability of pannexin 1 channels, and discuss their impact on acute epileptiform activity and chronic epilepsy according to the regime of activity and disease state. These data pave the way for the development of new antiepileptic strategies selectively targeting pannexin 1 channels in a context-dependent manner.