A quantized mechanism for activation of pannexin channels

Yu-Hsin Chiu, Xueyao Jin, Christopher B. Medina, Susan A. Leonhardt, Volker Kiessling, Brad C. Bennett, Shaofang Shu, Lukas K. Tamm, Mark Yeager, Kodi S. Ravichandran and Douglas A. Bayliss ()
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Yu-Hsin Chiu: University of Virginia School of Medicine
Xueyao Jin: University of Virginia School of Medicine
Christopher B. Medina: Immunology and Cancer Biology, University of Virginia School of Medicine
Susan A. Leonhardt: University of Virginia School of Medicine
Volker Kiessling: University of Virginia School of Medicine
Brad C. Bennett: University of Virginia School of Medicine
Shaofang Shu: University of Virginia School of Medicine
Lukas K. Tamm: University of Virginia School of Medicine
Mark Yeager: University of Virginia School of Medicine
Kodi S. Ravichandran: Immunology and Cancer Biology, University of Virginia School of Medicine
Douglas A. Bayliss: University of Virginia School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract Pannexin 1 (PANX1) subunits form oligomeric plasma membrane channels that mediate nucleotide release for purinergic signalling, which is involved in diverse physiological processes such as apoptosis, inflammation, blood pressure regulation, and cancer progression and metastasis. Here we explore the mechanistic basis for PANX1 activation by using wild type and engineered concatemeric channels. We find that PANX1 activation involves sequential stepwise sojourns through multiple discrete open states, each with unique channel gating and conductance properties that reflect contributions of the individual subunits of the hexamer. Progressive PANX1 channel opening is directly linked to permeation of ions and large molecules (ATP and fluorescent dyes) and occurs during both irreversible (caspase cleavage-mediated) and reversible (α1 adrenoceptor-mediated) forms of channel activation. This unique, quantized activation process enables fine tuning of PANX1 channel activity and may be a generalized regulatory mechanism for other related multimeric channels.

Date: 2017
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DOI: 10.1038/ncomms14324

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