Structural and functional analysis of human pannexin 2 channel

Zhihui He, Yonghui Zhao, Michael J. Rau, James A. J. Fitzpatrick, Rajan Sah, Hongzhen Hu () and Peng Yuan ()
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Zhihui He: Washington University School of Medicine
Yonghui Zhao: Washington University School of Medicine
Michael J. Rau: Washington University Center for Cellular Imaging, Washington University School of Medicine
James A. J. Fitzpatrick: Washington University School of Medicine
Rajan Sah: Washington University School of Medicine
Hongzhen Hu: Washington University School of Medicine
Peng Yuan: Washington University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-10

Abstract: Abstract The pannexin 2 channel (PANX2) participates in multiple physiological processes including skin homeostasis, neuronal development, and ischemia-induced brain injury. However, the molecular basis of PANX2 channel function remains largely unknown. Here, we present a cryo-electron microscopy structure of human PANX2, which reveals pore properties contrasting with those of the intensely studied paralog PANX1. The extracellular selectivity filter, defined by a ring of basic residues, more closely resembles that of the distantly related volume-regulated anion channel (VRAC) LRRC8A, rather than PANX1. Furthermore, we show that PANX2 displays a similar anion permeability sequence as VRAC, and that PANX2 channel activity is inhibited by a commonly used VRAC inhibitor, DCPIB. Thus, the shared channel properties between PANX2 and VRAC may complicate dissection of their cellular functions through pharmacological manipulation. Collectively, our structural and functional analysis provides a framework for development of PANX2-specific reagents that are needed for better understanding of channel physiology and pathophysiology.

Date: 2023
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DOI: 10.1038/s41467-023-37413-z

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