Abstract
Extracellular purines, such as ATP, act as ligands of P2X and P2Y receptors to modulate many important physiologies. The discovery of multiple ATP-releasing plasma membrane ion channels, such as CALHM1 and Pannexin 1 (Panx1), presents previously unappreciated mechanisms to activate purinergic signaling pathways. Panx1 channels are widely expressed in diverse types of vertebrate cells. The activity of Panx1 channels has been associated with multiple physiological conditions, such as regulations of blood pressure and immune responses; therefore, aberrant Panx1 activation has been implicated in various diseased conditions, including inflammation, seizure, and hypertension. However, our understanding about the biophysical properties and regulator)' mechanisms of Panx1 channels remain limited, and the pharmacology of these versatile ion channels has just begun to be explored. Here, we summarize the current evidence for the roles of Panx1 channels in different pathophysiological conditions, describe the unexpected activation mechanisms mediated by proteolytic cleavage of C-terminus and HDAC6-dependent lysine deacetylation, and we also examine recently discovered Panx1 inhibitors. Together, these findings could provide mechanistic insights for Panx1-related pathophysiologies and may present potential opportunities to develop future therapeutics for Panx1-related diseases.