Recent advances in the structure and activation mechanisms of metabolite-releasing Pannexin 1 channels.

Pannexin 1 (PANX1) is a widely expressed large-pore ion channel located in the plasma membrane of almost all vertebrate cells. It possesses a unique ability to act as a conduit for both inorganic ions (e.g. potassium or chloride) and bioactive metabolites (e.g. ATP or glutamate), thereby activating varying signaling pathways in an autocrine or paracrine manner. Given its crucial role in cell-cell interactions, the activity of PANX1 has been implicated in maintaining homeostasis of cardiovascular, immune, and nervous systems. Dysregulation of PANX1 has also been linked to numerous diseases, such as ischemic stroke, seizure, and inflammatory disorders. Therefore, the mechanisms underlying different modes of PANX1 activation and its context-specific channel properties have gathered significant attention. In this review, we summarize the roles of PANX1 in various physiological processes and diseases, and analyze the accumulated lines of evidence supporting diverse molecular mechanisms associated with different PANX1 activation modalities. We focus on examining recent discoveries regarding PANX1 regulations by reversible post-translational modifications, elevated intracellular calcium concentration, and protein-protein interactions, as well as by irreversible cleavage of its C-terminal tail. Additionally, we delve into the caveats in the proposed PANX1 gating mechanisms and channel open-closed configurations by critically analyzing the structural insights derived from cryo-EM studies and the unitary properties of PANX1 channels. By doing so, we aim to identify potential research directions for a better understanding of the functions and regulations of PANX1 channels.