Cryo-EM structures of the ATP release channel pannexin 1

Abstract

The plasma membrane ATP release channel pannexin 1 has been implicated in numerous physiological and pathophysiological processes associated with purinergic signaling, including cancer progression, apoptotic cell clearance, inflammation, blood pressure regulation, oocyte development, epilepsy and neuropathic pain. Here, we present nearatomic resolution structures of Xenopus tropicalis and Homo sapiens PANX1 determined by cryo-electron microscopy that reveal a heptameric channel architecture. Compatible with ATP permeation, the transmembrane pore and cytoplasmic vestibule are exceptionally wide. An extracellular tryptophan ring located at the outer pore creates a constriction site, potentially functioning as a molecular sieve that restricts the size of permeable substrates. In combination with functional characterization, this work elucidates the previously unknown architecture of pannexin channels and establishes a foundation for understanding their unique channel properties as well as for developing rational therapies..

Consideration of Pannexin 1 channels in COVID-19 pathology and treatment

“…In light of these prior findings, it could be valuable to determine whether, like tenofovir, remdesivir also impacts both PANX1 channel activity and possibly PANX1-associated inflammatory signaling in COVID-19. This work would be facilitated by the recent advances in our understanding of the PANX1 structure, including identification of key extracellular regulatory residues ( 16 , 39 ). Remdesivir’s effects on PANX1 channels are not known but would merit investigation in light of the blocking effect of the related drug, tenofovir, and the established role of PANX1 in inflammation and regulation of virus life cycles.…”

Single-cell dynamics of pannexin-1-facilitated programmed ATP loss during apoptosis

“…PANX1 belongs to the innexin/pannexin superfamily and forms a heptameric pore in the plasma membrane ( Deng et al, 2020 ; Michalski et al, 2020 ; Qu et al, 2020 ), functioning as a large-pore channel capable of passing small molecules ( Bao et al, 2004 ; Dahl and Muller, 2014 ; Panchin et al, 2000 ; Penuela et al, 2013 ). It has been reported that apoptotic cells release ATP, AMP, and also UTP through the PANX1 channel as ‘find-me’ signals to attract macrophages and that the PANX1 channel is opened by caspase-3/7, which cleaves the C-terminal region of the channel ( Chekeni et al, 2010 ; Elliott et al, 2009 ; Yamaguchi et al, 2014 ).…”

Single-cell dynamics of pannexin-1-facilitated programmed ATP loss during apoptosis

“…PANX1 belongs to the innexin/pannexin superfamily and forms a heptameric pore in the plasma membrane (Deng et al, 2020; Michalski et al, 2020; Qu et al, 2020), functioning as a large-pore channel capable of passing small molecules (Bao et al, 2004; Dahl and Muller, 2014; Panchin et al, 2000; Penuela et al, 2013). It has been reported that apoptotic cells release ATP, AMP, and also UTP through the PANX1 channel as “find-me” signals to attract macrophages and that the PANX1 channel is opened by caspase-3/7, which cleaves the C-terminal region of the channel (Chekeni et al, 2010; Elliott et al, 2009; Yamaguchi et al, 2014).…”