1.A.25.2.2
Pannexin1 and pannexin2 (pannexin-2; pannexin 2) channels show quaternary similarities to connexons but different oligomerization numbers (Ambrosi et al., 2010). Pannexin 1 (Px1, Panx1) and pannexin 2 (Px2, Panx2) underlie channel function in neurons and contribute to ischemic brain damage (Bargiotas et al., 2011). PANX2 channels participate in multiple physiological processes including skin homeostasis, neuronal development, and ischemia-induced brain injury. He et al. 2023 presented a cryo-EM structure of human PANX2, which revealed 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 (TC# 1.A.25.3.1), rather than PANX1. Furthermore, PANX2 displays a similar anion permeability sequence as VRAC, and PANX2 channel activity is inhibited by a commonly used VRAC inhibitor, DCPIB. The shared channel properties between PANX2 and VRAC may complicate dissection of their cellular functions through pharmacological manipulation (He et al. 2023). The cryo-EM structure of the human heptameric PANX2 channel has been solved (Zhang et al. 2023). It is a large-pore ATP-permeable channel with critical roles in various physiological processes, such as the inflammatory response, energy production and apoptosis. Its dysfunction is related to numerous pathological conditions including ischemic brain injury, glioma and glioblastoma multiforme. The structure was solved at a resolution of 3.4 Å. The Panx2 structure assembles as a heptamer, forming an exceptionally wide channel pore across the transmembrane and intracellular domains, compatible with ATP permeation. Comparing Panx2 with Panx1 structures in different states reveals that the Panx2 structure corresponds to an open channel state. A ring of seven arginine residues located at the extracellular entrance forms the narrowest site of the channel, which serves as the critical molecular filter controlling the permeation of substrate molecules. This was further verified by molecular dynamics simulations and ATP release assays. These studies revealed the architecture of the Panx2 channel and provided insights into the molecular mechanism of its channel gating (Zhang et al. 2023).