The 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 (Trp74). 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.
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September 2015
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Research Article|
September 04 2015
ATP stimulates pannexin 1 internalization to endosomal compartments
Andrew K.J. Boyce;
Andrew K.J. Boyce
*Division of Medical Sciences and Island Medical Program, University of Victoria, Victoria, Canada V8P 5C2
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Michelle S. Kim;
Michelle S. Kim
*Division of Medical Sciences and Island Medical Program, University of Victoria, Victoria, Canada V8P 5C2
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Leigh E. Wicki-Stordeur;
Leigh E. Wicki-Stordeur
*Division of Medical Sciences and Island Medical Program, University of Victoria, Victoria, Canada V8P 5C2
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Leigh Anne Swayne
Leigh Anne Swayne
1
*Division of Medical Sciences and Island Medical Program, University of Victoria, Victoria, Canada V8P 5C2
†Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, Canada V6T 1Z3
1To whom correspondence should be addressed (email lswayne@uvic.ca).
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Publisher: Portland Press Ltd
Received:
December 19 2014
Revision Received:
July 17 2015
Accepted:
July 20 2015
Accepted Manuscript online:
July 20 2015
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2015 Authors; published by Portland Press Limited
2015
Biochem J (2015) 470 (3): 319–330.
Article history
Received:
December 19 2014
Revision Received:
July 17 2015
Accepted:
July 20 2015
Accepted Manuscript online:
July 20 2015
Connected Content
A commentary has been published:
Interdependence of ATP signalling and pannexin channels; the servant was really the master all along?
Citation
Andrew K.J. Boyce, Michelle S. Kim, Leigh E. Wicki-Stordeur, Leigh Anne Swayne; ATP stimulates pannexin 1 internalization to endosomal compartments. Biochem J 15 September 2015; 470 (3): 319–330. doi: https://doi.org/10.1042/BJ20141551
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