Mechanism of gating by calcium in connexin hemichannels

Abstract

Significance Connexin channels are ubiquitous, providing pathways for movement of molecules between cells (junctional channels) and for release of molecular effectors into the extracellular environment (plasma membrane hemichannels). To maintain an adequate permeability barrier, hemichannels are tightly regulated by normal extracellular Ca 2+ to be closed under most conditions. Connexin mutations that disrupt hemichannel regulation by Ca 2+ cause human pathologies due to aberrantly open hemichannels. Here we elucidate molecular mechanisms of gating by Ca 2+ in hemichannels: Ca 2+ binding causes a reorganization of specific interactions within the connexin protein that lead to a closed channel. Further, we show that the actual “gate” is deeper into the pore from where Ca 2+ binds. The interactions involved are conserved across connexins, pointing to a general mechanism.