Regulation of connexin- and pannexin-based channels by post-translational modifications

Connexin (Cx) and pannexin (Panx) proteins form large conductance channels, which function as regulators of communication between neighbouring cells via gap junctions and/or hemichannels. Intercellular communication is essential to coordinate cellular responses in tissues and organs, thereby fulfilling an essential role in the spreading of signalling, survival and death processes. The functional properties of gap junctions and hemichannels are modulated by different physiological and pathophysiological stimuli. At the molecular level, Cxs and Panxs function as multi-protein channel complexes, regulating their channel localisation and activity. In addition to this, gap junctional channels and hemichannels are modulated by different post-translational modifications (PTMs), including phosphorylation, glycosylation, proteolysis, N-acetylation, S-nitrosylation, ubiquitination, lipidation, hydroxylation, methylation and deamidation. These PTMs influence almost all aspects of communicating junctional channels in normal cell biology and pathophysiology. In this review, we will provide a systematic overview of PTMs of communicating junction proteins and discuss their effects on Cx and Panx-channel activity and localisation

The Cellular Life of Pannexins

The mammalian pannexin family of channel-forming proteins consisting of Panx1, Panx2, and Panx3 has received considerable attention in the last 10 years given their newly discovered physiological roles in development and disease. Pannexins exhibit diverse subcellular profiles indicating that they may serve distinct roles in cells and tissues of different origin. This complexity in cellular residencies may be rooted in the fact that pannexin genes consist of multiple exons that have led to the identification of several splice variants. Additionally, post-translational modifications, especially N-glycosylation, appear to be important in regulating trafficking and intermixing of pannexin family members increasing the diversity of assembled channels. These long-lived membrane proteins are typically trafficked through the classical secretory pathway before reaching the plasma membrane although Panx2 tends to often be retained in intracellular compartments. Trafficking, stability, and function of pannexins likely enlist the services of an interactome that continues to expand. The research field has been amazed by the fact that Panx1 null mice are generally healthy with distinct phenotypes only being revealed when mutant mice encounter additional stress or have comorbidities. The emerging field of pannexin biology has also begun to explore the relationships and potential cross-talk between pannexin channels and connexin hemichannels. It is imperative to dissect the different constituents of the channels and the molecules that pass through these distinct channel types. Finally, as witnessed in connexin biology throughout the 90s, the field awaits to see if germline mutations in the genes that encode pannexins also cause disease

Pannexin 1 Constitutes the Large Conductance Cation Channel of Cardiac Myocytes

A large conductance (∼300 picosiemens) channel (LCC) of unknown molecular identity, activated by Ca2+ release from the sarcoplasmic reticulum, particularly when augmented by caffeine, has been described previously in isolated cardiac myocytes. A potential candidate for this channel is pannexin 1 (Panx1), which has been shown to form large ion channels when expressed in Xenopus oocytes and mammalian cells. Panx1 function is implicated in ATP-mediated auto-/paracrine signaling, and a crucial role in several cell death pathways has been suggested. Here, we demonstrate that after culturing for 4 days LCC activity is no longer detected in myocytes but can be rescued by adenoviral gene transfer of Panx1. Endogenous LCCs and those related to expression of Panx1 share key pharmacological properties previously used for identifying and characterizing Panx1 channels. These data demonstrate that Panx1 constitutes the LCC of cardiac myocytes. Sporadic openings of single Panx1 channels in the absence of Ca2+ release can trigger action potentials, suggesting that Panx1 channels potentially promote arrhythmogenic activities