ATP stimulates pannexin 1 internalization to endosomal compartments

dc.contributor.authorBoyce, Andrew K.J.
dc.contributor.authorKim, Michelle S.
dc.contributor.authorWicki-Stordeur, Leigh E.
dc.contributor.authorSwayne, Leigh Anne
dc.descriptionATP stimulates internalization of Panx1. This novel finding raises important considerations with regards to Panx1 surface stability in diverse scenarios in which ATP can be rapidly elevated in the extracellular space.en_US
dc.description.abstractThe ubiquitous pannexin 1 (Panx1) ion- and metabolite-permeable channel mediates the release of ATP, a potent signalling molecule. In the present study, we provide striking evidence that ATP, in turn, stimulates internalization of Panx1 to intracellular membranes. These findings hold important implications for understanding the regulation of Panx1 when extracellular ATP is elevated. In the nervous system, this includes phenomena such as synaptic plasticity, pain, precursor cell development and stroke; outside of the nervous system, this includes things like skeletal and smooth muscle activity and inflammation. Within 15 min, ATP led to significant Panx1-EGFP internalization. In a series of experiments, we determined that hydrolysable ATP is the most potent stimulator of Panx1 internalization. We identified two possible mechanisms for Panx1 internalization, including activation of ionotropic purinergic (P2X) receptors and involvement of a putative ATP-sensitive residue in the first extracellular loop of Panx1 (Trp(74)). Internalization was cholesterol-dependent, but clathrin, caveolin and dynamin independent. Detailed analysis of Panx1 at specific endosome sub-compartments confirmed that Panx1 is expressed in endosome membranes of the classical degradation pathway under basal conditions and that elevation of ATP levels diverts a sub-population to recycling endosomes. This is the first report detailing endosome localization of Panx1 under basal conditions and the potential for ATP regulation of its surface expression. Given the ubiquitous expression profile of Panx1 and the importance of ATP signalling, these findings are of critical importance for understanding the role of Panx1 in health and disease.en_US
dc.description.sponsorshipThis work was supported by operating grant support to L.A.S. from the Natural Sciences and Engineering Research Council (NSERC) [grant number 402270-2011]; infrastructure support from the Canadian Foundation for Innovation (CFI) [grant number 29462]; and the BC Knowledge Development Fund (BCKDF) [grant number 804754]. L.A.S. was also supported by a salary grant from the Michael Smith Foundation for Health Research (MSFHR) [grant number 5900]. Student scholarships were awarded to A.K.J.B. from NSERC [grant number PGSD 459931-2014] and from the University of Victoria President’s Research Scholarship), to M.S.K. from NSERC (USRA), and to L.E.W.-S. from NSERC [grant number Vanier Canada Graduate Scholarship CGV-NSERC-00184].en_US
dc.identifier.citationBoyce, A.K.J., Kim, M.S., Wicki-Stordeur, L.E. & Swayne, L.A. (2015). ATP stimulates pannexin 1 internalization to endosomal compartments. Biochemical Journal, 470(3), 319-330.en_US
dc.publisherBiochemical Journalen_US
dc.subjectadenosine 5′-triphosphate (ATP)en_US
dc.subjectpannexin 1en_US
dc.titleATP stimulates pannexin 1 internalization to endosomal compartmentsen_US


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