Exciting and not so exciting roles of pannexins

Abstract

It is the current view that purinergic signaling regulates many physiological functions. Pannexin1 (Panx1), a member of the gap junction family of proteins is an ATP releasing channel that plays important physio-pathological roles in various tissues, including the CNS. Upon binding to purinergic receptors expressed in neural cells, ATP triggers cellular responses including increased cell proliferation, cell morphology changes, release of cytokines, and regulation of neuronal excitability via release of glutamate, GABA and ATP itself. Under pathological conditions such as ischemia, trauma, inflammation, and epilepsy, extracellular ATP concentrations increases drastically but the consequences of this surge is still difficult to characterize due to its rapid metabolism in ADP and adenosine, the latter having inhibitory action on neuronal activity. For seizures, for instance, the excitatory effect of ATP on neuronal activity is mainly related to its action of P2X receptors, while the inhibitory effects are related to activation of P1, adenosine receptors. Here we provide a mini review on the properties of pannexins with a main focus on Panx1 and its involvement in seizure activity. Although there are only few studies implicating Panx1 in seizures, they are illustrative of the dual role that Panx1 has on neuronal excitability.

Keywords: Epilepsy; Gap junctions; P2X receptors; Panx1; Purinergic signaling; Seizures.

Figure 1. Schematics of pannexins’ membrane topologies and post-translational modification sites

The three pannexins (Panx1, Panx2, and Panx3) are tetraspan membrane proteins with cytosolic N- and C-termini and two extracellular and one intracellular loops. N-glycosylation sites (green circles) are shown on the second extracellular loop of Panx1 and on the first extracellular loop of Panx2 and Panx3. Two nitrosylation (red circles) and one caspase cleavage (yellow circle) sites are shown for Panx1.

Figure 2. Schematics of hypothesized excitatory and inhibitory roles of Panx1 in regulating neuronal excitability

Excitatory (A, B) and inhibitory (C, D) roles of Panx1. (A) Activation of NMDA receptors (1) leads via a Src tyrosine kinase (2) to the opening of Panx1 channels (3) which generate the NMDA receptor secondary currents and thus contribute to epileptiform activity [52, 53, 78]. (B) Elevated extracellular K⁺ concentration (1), resultant from KA-induced seizures, activates Panx1 channels directly; ATP released from Panx1 channels (2) activates P2X7 receptors (3) which via a Src tyrosine kinase (4), further promote the opening of Panx1 channels in a positive feedback loop that sustain and prolong seizure activity [33, 34, 51]. (C) Activation of muscarinic M1 receptors (1) leads, via elevation of intracellular Ca²⁺, to the opening of Panx1 channels (2) and subsequent release of ATP; activation of P2X7 receptors (3) then leads, via PKC (4), to M1 desensitization and consequent reduction of seizure activity [77]. (D) Moderate hypoglycemia (1) leads to opening of Panx1 channels (2) and release of ATP. Ecto-nucleotidases (CD39/CD73) then dephosphorylate ATP into adenosine (3) which activates adenosine A1 receptors (4) that are linked to K_ATP channels (5) leading to the efflux of K⁺ and consequent silencing of neurons [81].