Regulation of Pannexin 1 Surface Expression by Extracellular ATP: Potential Implications for Nervous System Function in Health and Disease

Abstract

Pannexin 1 (Panx1) channels are widely recognized for their role in ATP release, and as follows, their function is closely tied to that of ATP-activated P2X7 purinergic receptors (P2X7Rs). Our recent work has shown that extracellular ATP induces clustering of Panx1 with P2X7Rs and their subsequent internalization through a non-canonical cholesterol-dependent mechanism. In other words, we have demonstrated that extracellular ATP levels can regulate the cell surface expression of Panx1. Here we discuss two situations in which we hypothesize that ATP modulation of Panx1 surface expression could be relevant for central nervous system function. The first scenario involves the development of new neurons in the ventricular zone. We propose that ATP-induced Panx1 endocytosis could play an important role in regulating the balance of cell proliferation, survival, and differentiation within this neurogenic niche in the healthy brain. The second scenario relates to the spinal cord, in which we posit that an impairment of ATP-induced Panx1 endocytosis could contribute to pathological neuroplasticity. Together, the discussion of these hypotheses serves to highlight important outstanding questions regarding the interplay between extracellular ATP, Panx1, and P2X7Rs in the nervous system in health and disease.

Pannexin 1 Regulates Dendritic Protrusion Dynamics in Immature Cortical Neurons

“…A germline PANX1 SNP was associated with intellectual disability ( Shao et al, 2016 ). PANX1 is also linked to neurodevelopmental disorders indirectly through its interacting partner CRMP2 and its downstream signaling effectors and interactors, purinergic receptors ( Boyce et al, 2015 ; Boyce and Swayne, 2017 ; for review, see Swayne and Boyce, 2017 ). CRMP2 auto-antibodies have been implicated in ASD ( Braunschweig et al, 2013 ), and brain-specific deletion of the gene encoding for CRMP2 resulted in decreased dendritic spine density and reduced LTP ( Zhang et al, 2016 ), while suramin treatment corrected synaptic and behavioral phenotypes in the Fmr1 KO mouse ( Naviaux et al, 2013 , 2015 , 2017 ).…”

Pannexin 1 Regulates Network Ensembles and Dendritic Spine Development in Cortical Neurons

“…More recent work showed that Panx1 channels are strongly active under ictal conditions in human brain cortical tissue from epilepsy patients and in the CA1 region of the hippocampus following kainic acid seizure induction (Dossi et al, 2018), suggesting that in pathologic conditions Panx1 is positively correlated with excitability; although the mechanistic underpinnings, such as the possible interneuronal or glial contributions to this effect, have not yet been fully resolved. Relatedly, because Panx1 has been detected in multiple cell types and has been associated with cell death processes (for review, see Sandilos and Bayliss, 2012; Thompson, 2015; Swayne and Boyce, 2017), we analyzed the cellular composition and viability of our cortical cultures. WT and Panx1 KO cultures were comprised of similar percentages of excitatory neurons, inhibitory neurons and astrocytes.…”

Pannexin-1 channel opening is critical for COVID-19 pathogenesis

“…Normally, Panx-1 channels exist in a closed state in healthy conditions (Pelegrin and Surprenant, 2006;Saez et al, 2010;Seror et al, 2011;Swayne and Boyce, 2017). Thus, targeting Panx-1 opening could have minimal side effects in healthy individuals and prevent viral infection and spread generated by multiple SARS-CoV-2 variants.…”