Abstract
The pannexin family of channels consists of three members—pannexin-1 (Panx1), pannexin-2 (Panx2), and pannexin-3 (Panx3) that enable the exchange of metabolites and signaling molecules between intracellular and extracellular compartments. Pannexin-mediated release of intracellular ATP into the extracellular space has been tied to a number of cellular activities, primarily through the activity of type P2 purinergic receptors. Previous work indicates that the opening of Panx1 channels and activation of purinergic receptors by extracellular ATP may cause inflammation and apoptosis. In the CNS (central nervous system) and PNS (peripheral nervous system), coupled pannexin, and P2 functions have been linked to peripheral sensitization (pain) pathways. Purinergic pathways are also essential for other critical processes in the PNS, including myelination and neurite outgrowth. However, whether such pathways are pannexin-dependent remains to be determined. In this study, we use a Panx1 knockout mouse model and pharmacological inhibitors of the Panx1 and the ATP-mediated signaling pathway to fill gaps in our understanding of Panx1 localization in peripheral nerves, roles for Panx1 in axonal outgrowth and myelination, and neurite extension. Our data show that Panx1 is localized to axonal, myelin, and vascular compartments of the peripheral nerves. Knockout of Panx1 gene significantly increased axonal caliber in vivo and axonal growth rate in cultured dorsal root ganglia (DRG) neurons. Furthermore, genetic knockout of Panx1 or inhibition of components of purinergic signaling, by treatment with probenecid and apyrase, resulted in denser axonal outgrowth from cultured DRG explants compared to untreated wild-types. Our findings suggest that Panx1 regulates axonal growth in the peripheral nervous system.
Highlights
The pannexin family of channels consists of three members—Panx1, 2, and 3—that enable the exchange of metabolites and signaling molecules between intracellular and extracellular compartments
Pannexin Modulates Peripheral Neuron Outgrowth has been tied to a number of cellular activities, primarily through the activity of type P2 purinergic receptors, which elicit adenosine triphosphate (ATP)-initiated ionotropic (P2X) or metabotropic (P2Y) cellular responses depending on the receptor subtype (Penuela et al, 2013; Makarenkova and Shestopalov, 2014)
This study represents the first evaluation of the expression and localization of Panx1 protein in peripheral nerves, and assessment of the role of Panx1 on axonal morphology and outgrowth
Summary
The pannexin family of channels consists of three members—Panx , and 3—that enable the exchange of metabolites and signaling molecules between intracellular and extracellular compartments. Several cell types, including neurons, satellite glial cells, and hematopoietic cells of the DRG are believed to contribute to pannexin-mediated peripheral pain pathways (Huang et al, 2013; Retamal et al, 2014; Zhang et al, 2015; Weaver et al, 2017), and there is significant cross-talk among these cells, as demonstrated by interactions between glial cells and neuronal cell bodies within sensory and other ganglia (Huang et al, 2013; Shibukawa et al, 2015; Spray and Hanani, 2017). Pannexin participation is hypothesized to occur via coupling with P2 receptor activity (Huang et al, 2013; Zhang et al, 2015), including P2X7 and P2X4 (Hung et al, 2012; Kawano et al, 2012), based on evidence for pannexin/P2 interactions in central sensitization pathways (Fabbretti, 2013; Bravo et al, 2014, 2015) and in sensory signaling pathways within sensory ganglia (Huang et al, 2013; Spray and Hanani, 2017)
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