Not what you thought: How H+ ions combine with taurine or other aminosulfonates to close Cx26 channels

377 C o m m e n t a r y Gap junctions are aggregates of microscopic channels that connect the cytoplasmic compartments of the coupled cells. A gap junction channel is formed of two hemichannels, one contributed by each cell. Hemichan-nels can be formed in a post-Golgi compartment and transported to the cell surface in vesicles that fuse with the external membrane (Musil and Goodenough, 1993). Hemichannels then find a hemichannel in an apposed membrane and dock to form a cell–cell channel. For a long time, hemichannels were thought not to open to the exterior and to open only when joined to a hemi-channel from an apposed membrane. Electrophysio-logical measurements showed that the hemichannels forming the first cell–cell channel had not been open to the medium before the channel formed (Bukauskas and Weingart, 1993). A teleological argument was that if hemichannels had the same large diameter pore as in a cell channel, they would have provided a deleterious link with the external medium, allowing loss of K + , ATP, and other metabolites and influx of Ca 2+ and Na +. Now it is clear that isolated, unapposed hemichannels can open under specific physiological as well as pathological conditions, and metabolites coming out through hemichannels can mediate paracrine as well as auto-crine signaling (Sáez et al., 2010). The open probability is generally low, and increased opening can contribute to cell death, as presumed in arguing that the hemi-channels should not open. Gap junctions are regulated at the levels of gene transcription , RNA translation, membrane insertion, cell–cell channel formation, channel gating, and degradation. For the electrophysiologist, channel gating is perhaps the most attractive of the regulatory processes, and it represents a relatively fast and reversible means of control of intercellular communication. Gap junction channels are usually maximally open at zero transjunc-tional voltage, V j , and gating to a closed state can be induced by V j , low cytoplasmic pH, high cytoplasmic pCa, and various exogenous blocking agents such as long chain alcohols, carbenoxolone, oleamide, and meflo-quine. Gating agents that have been examined in this respect decrease conductance by reducing open probability ; unitary conductance of open channels is not affected. Admittedly, the pharmacology is not very clean, and the available blocking agents are somewhat nonspecific. In most cases, junctional conductance, g j , is dependent on V j and independent of the voltage between the inside of …