Structure versus function: Are new conformations of pannexin 1 yet to be resolved?

Abstract

Pannexin 1 (Panx1) plays a decisive role in multiple physiological and pathological settings, including oxygen delivery to tissues, mucociliary clearance in airways, sepsis, neuropathic pain, and epilepsy. It is widely accepted that Panx1 exerts its role in the context of purinergic signaling by providing a transmembrane pathway for ATP. However, under certain conditions, Panx1 can also act as a highly selective membrane channel for chloride ions without ATP permeability. A recent flurry of publications has provided structural information about the Panx1 channel. However, while these structures are consistent with a chloride selective channel, none show a conformation with strong support for the ATP release function of Panx1. In this Viewpoint, we critically assess the existing evidence for the function and structure of the Panx1 channel and conclude that the structure corresponding to the ATP permeation pathway is yet to be determined. We also list a set of additional topics needing attention and propose ways to attain the large-pore, ATP-permeable conformation of the Panx1 channel.

Mechanosensitive Pannexin 1 Activity Is Modulated by Stomatin in Human Red Blood Cells

“…The heptameric structure of PANX1 has been recently solved [ 6 , 7 , 8 , 9 , 10 , 11 ], giving new insights into the channel conformation though none of the presented structures could provide a precise visualization of the CT tail. Moreover, the CT tail cleavage cannot explain the PANX1 function under most physiological situations [ 12 ], where PANX1 is reversibly activated by several ligands in the absence of caspase activation. Such a mode of pore activation might entail a displacement of the CT tail due to sequential posttranslational modifications and/or binding of diverse stimuli on PANX1 subunits [ 12 , 13 ].…”

“…Moreover, the CT tail cleavage cannot explain the PANX1 function under most physiological situations [ 12 ], where PANX1 is reversibly activated by several ligands in the absence of caspase activation. Such a mode of pore activation might entail a displacement of the CT tail due to sequential posttranslational modifications and/or binding of diverse stimuli on PANX1 subunits [ 12 , 13 ]. Alternatively, conformational changes in other parts of the macromolecule might participate in the gating mechanism.…”

Lytic Release of Cellular ATP: Physiological Relevance and Therapeutic Applications

“…ATP-conducting properties have been functionally established for the voltage-dependent anion channel (VDAC) of the outer mitochondrial membrane by recording single-channel ATP-mediated currents [12], and much supportive evidence also exists for a porin-like maxi-Cl -channels [13,14]. It remains contentious, however, for several other channel candidates where definite evidence based on patch-clamp electrophysiology is still missing [13,15]. These suppositions may, at least in part, arise from the often underestimated or neglected "conductive component" of ATP release due to cell membrane damage and cell lysis.…”

Panx1b Modulates the Luminance Response and Direction of Locomotion in the Zebrafish

“…It is widely accepted that Panx1 provide a transmembrane pathway for ATP [ 1 ]. However, under certain conditions, Panx1 can also act as a highly selective membrane channel for chloride ions without ATP permeability [ 2 ]. The cryoEM structure of Panx1 as a heptameric selective chloride channels was resolved recently [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ].…”

“…However, under certain conditions, Panx1 can also act as a highly selective membrane channel for chloride ions without ATP permeability [ 2 ]. The cryoEM structure of Panx1 as a heptameric selective chloride channels was resolved recently [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ]. The expression of Panx1 in the rodent eye has fostered research on functional implications in the normal retina physiology and pathologies related to ocular hypertension or ischemia in mouse models [ 9 , 10 , 11 , 12 , 13 ].…”