Lateralized gap junctions in pulmonary hypertension: lost but not alone

t f f t c c i o s g i p c w t l a It has long been recognized that some states of cardiac disease are associated with a dislocation of gap junctions from the intercalated disc (ID) to the lateral sides, known as gap junction lateralization or disarray (for recent review, see Fontes et al). Lateralization was first directly linked to arrhythmia in the border zone of healing infarcts, where Peters et al showed that areas prone to inducible arrhythmia also exhibited gap junction lateralization. It is, however, still uncertain what causes the dislocation of gap junctions, how they get there, and whether lateralization is arrhythmogenic per se. In this issue of HeartRhythm, Chkourko et al show that pulmonary hypertension is associated with the lateralization of not only the connexins making up the gap junction channels but also a number of structural proteins that are normally located at the ID and proteins involved in the transport of connexin 43 (Cx43, the most abundant cardiac gap junctional protein) to the plasma membrane. Cx43 can be transported along microtubules, and recently it was shown that the microtubule-associated protein EB1 is essential for correct trafficking of Cx43 to the ID. The study also showed that EB1 disappears from the ID during ischemia, abrogating the trafficking of Cx43 to the disc. The study by Chkourko et al shows that EB1 is most ikely responsible for redirecting Cx43 to the lateral memranes during remodeling in pulmonary hypertension. The inking of EB1 to the membrane is reported to involve everal components ending with N-cadherin as the memrane anchor. Does this imply that N-cadherin is the first omponent to arrive at the lateral membrane? Maybe in the ase of pulmonary hypertension, but in some models of gap unction lateralization, N-cadherin stays at the ID (eg, see olussi et al). Still, N-cadherin remains an interesting andidate, raising the question why it translocates. Recent vidence implies that cadherins are involved in mechanoensing at cell-to-cell interfaces and maybe cadherin-de