Gating on the outside

Connexin protein can form single-membrane spanning channels (called hemichannels or connexons) that can dock with each other to span two closely apposed plasma membranes and thereby create gap junction channels. What keeps unapposed connexin hemichannels closed, and how do they open when part of junctional channels? The report from Tang et al. (2009) in this issue (see p. 555), along with a recent publication from several of the same authors, goes a long way toward answering the first question and allows more specific questions to be asked regarding the second. The recently published crystal structure of a connexin channel informs both. A hemichannel is a hexamer of connexin protein. Each connexin monomer has four transmembrane domains (TM1–TM4) with the amino and carboxyl termini cytoplasmic. The extracellular aspect of the hemichannel is composed of two extracellular loops (E1 and E2) from each connexin monomer. Unapposed hemichannels are able to open under certain conditions but must remain closed most of the time to maintain the plasma membrane permeability barrier. The gating mechanism that achieves this is voltage sensitive and requires extracellular calcium ion in the millimolar range to remain closed at normal resting potentials (Ebihara and Steiner, 1993; Trexler et al., 2000; Ebihara et al., 2003; Puljung et al., 2004; Verselis and Srinivas, 2008). This mechanism has acquired the eponym “loop gating” because of the composition of the extracellular domains, the effect of extracellular but not intracellular calcium ion on its function, and because at the singlechannel level, the gating transitions resemble those that occur when a junctional channel forms (i.e., when the loop domains from apposed hemichannels interact) (Trexler et al., 1996). These transitions are distinct from those seen in other types of connexin channel gating. In addition to remaining mostly closed when unapposed, the loop gate must also be able to open when docked to another hemichannel in the junctional configuration. The relationship between loop gating and the mechanism/structure of hemichannel docking is unclear; the two processes likely involve the same or adjacent portions of the protein, which raises intriguing