Carboxyl terminus of Pannexin-1 plays a crucial role in P2X7 receptor- mediated signaling

The cellular implications of the interaction between Pannexin-1 (Panx1) channel and P2X7 receptor (P2X7R) have not been fully elucidated. Evidence suggests that ATP, released through Panx1, activates P2X7R, which in turn promotes further activation of Panx1. In a previous study, we reported that the C -terminus of Panx1 (Panx1-CT) attenuates P2X7R-mediated Ca2+ influx and cell death. One of the distinctive features of P2X7R is the gradual increase in current with repetitive stimulation. In the current study, we report an effect of Panx1-CT (amino acid residues 350 to 426) on P2X7R current, which differs from the effect of full-length Panx1. Panx1-CT inhibited P2X7R current, which persisted in all consecutive agonist applications. However, full-length Panx1 reduced P2X7R current at initial stimulations, followed by gradual augmentation. When P2X7R was activated for an extended period, cells expressing Panx1-CT exhibited less mitochondrial depolarization, reactive oxygen species (ROS) generation, Caspase 3 acti-vation and cell death, whereas cells overexpressing full-length Panx1 showed the opposite effect. Taken together, these findings suggest that Panx1 can either attenuate or augment P2X7R-mediated cellular processes depending on the degree of P2X7R activation. (c) 2023 Elsevier Inc. All rights reserved.

Automated summary

The interaction between Pannexin-1 (Panx1) channel and P2X7 receptor (P2X7R) has important cellular implications. ATP released through Panx1 activates P2X7R, which further activates Panx1. Previous studies have shown that Panx1-CT attenuates P2X7R-mediated Ca2+ influx and cell death. In this study, it was found that Panx1-CT inhibits P2X7R current, while full-length Panx1 initially reduces P2X7R current and then gradually increases it. Furthermore, Panx1-CT expression reduces mitochondrial depolarization, reactive oxygen species generation, Caspase 3 activation, and cell death, whereas overexpression of full-length Panx1 has the opposite effect. These findings indicate that Panx1 can modulate P2X7R-mediated cellular processes depending on the degree of P2X7R activation.