Gap junctions in preconditioning against arrhythmias.

Ischemic preconditioning is a natural mechanism by which brief periods of ischemia–reperfusion initiate a complex cascade of events that culminate in the protection of the heart against a subsequent sustained ischemia, reducing infarct size, postischemic dysfunction, and the incidence of arrhythmias [1]. In essence, endogenous or exogenous triggers released during ischemic or pharmacological preconditioning activate mediators that act on end-effectors, preserving mitochondrial, cytoskeletal, and cell membrane integrity [2]. However, although much effort has been dedicated to the study of preconditioning mechanisms, these have not been clearly elucidated, and in particular the pathways involved in the protection against arrhythmias have not been as thoroughly investigated as those concerning infarct size. One of the proposed targets of preconditioning protection is gap junctions. These intercellular structures formed by two hemichannels of connexin-43 (Cx43) mediate the exchange of small molecules and ions between two adjacent cells and play an active role in the electrical synchronization of the heart. Phosphorylation of Cx43 regulates gap junction conductance and permeability. In the normoperfused heart, most Cx43 is phosphorylated, allowing cell-to-cell coupling and the propagation of depolarization in the myocardial syncytium. During the course of ischemia, however, decreased ATP levels, increased intracellular Ca concentrations, and acidosis determine gap junction closure through Cx43 dephosphorylation and internalization into the cytosol. The proportion of functional gap junctions is thus reduced, inducing cellular uncoupling manifested by enhanced tissue