Molecular Determinants of Gap Junction Channels Conductance

Abstract

Gap junction (GJ) channels are formed by two hemichannels, each contributed by the cells taking part in this direct cell-cell communication conduit. These hydrophilic protein channels mediate the transfer of small cytoplasmic molecules between adjacent cells, such as ions and metabolites including second messengers. GJ channels formed by protein monomers, called connexins, are found in most cell types in vertebrates. These ubiquitous yet specific proteins form poorly selective channels with unique properties, and differ in their ability to mediate the transfer of specific molecules. In order to provide insight into molecular determinants of GJ channels conductance, we used molecular crystal structures of Connexin 26 (Cx26, also known as GJB2), PDB ID: 2ZW3, and Connexin 50 (Cx50, also known as GJA8), PDB ID: 6MHY. Molecular dynamics simulations were conducted with an external applied electric field to test intercellular communication via these channels evaluating conductance and selectivity. We compared pore radius and electrostatic profiles of both channels. Also, we compared the values of the conductance estimated by the observed permeation events with those reported in the literature. Our preliminary results suggest that electrostatic profile is a key determinant of ion selectivity and conductance. GJ channels formed by Cx26 show fewer diffusion events than those formed by Cx50, which corresponds with conductance values reported in the literature. Finally, we identified energy barriers for passage of ions through each channel and elucidated the effect of pore structure on energy barriers. This work was supported by the following grants: CONICYT PFCHA/Doctorado 21161628 (to C. Pareja-Barrueto),FONDECYT Regular 1170733 and ICM-MINECON P09-022-F (to D. Gonzalez-Nilo and J. C. Sáez), Anillo ATC71 and FONDECYT Regular 1191329 (to J. C. Sáez).