Pannexin 1 plays a pro-survival role by attenuating P2X7 receptor-mediated Ca2+ influx

Abstract

Extracellular ATP works as an autocrine and/or paracrine signaling molecule by activating plasma membrane-localized purinergic receptors. Stimulation of purinergic P2X7 receptor (P2X7R) increases cytosolic Ca2+ ([Ca2+]c), which in turn activates Pannexin 1 (Panx1) channel. In earlier studies, Panx1 and P2X7R have been shown to interact physically. Also, both the channels have been implicated in similar pathophysiological processes. In this study, we investigated the effect of Panx1 on P2X7R-mediated Ca2+influx. Panx1 attenuated P2X7R-mediated [Ca2+]c rise in CHO-K1 and HEK-293 cells. [Ca2+]c rise was higher in Panx1 knockdown astrocytes. The inhibitory effect was unaffected in the presence of Panx1 blocker, carbenoxolone. The region between 350th and 386th amino acid residues in the carboxyl terminus (CT) of Panx1 was found to be crucial for inhibiting P2X7R. Like full-length Panx1, the CT (350th to 426th amino acids) alone was able to attenuate the [Ca2+]c rise. Further, CT prevented cell death caused by P2X7R overactivation. Based on our results, we propose a novel pro-survival role of Panx1 exerted by modulating P2X7R.