Exploring the Membrane Potential of Simple Dual-Membrane Systems as Models for Gap-Junction Channels

Abstract

The conductance of ion channels can be modulated by a transmembrane potential difference, due to alterations on ion-mobility and also by changes in the pore structure. Despite the vast knowledge regarding the influence of voltage on transport properties of ion channels, little attention has been paid to describe, with atomic detail, the modulation of ionic transport in gap-junction channels (GJCs). Hence, molecular dynamics simulations were performed to explore the conductance of simple dual-membrane systems that account for the very basic features of GJCs. In doing so, we studied the influence of different charge distributions in the channel surface on these idealized systems under external electric fields, paying attention to the behavior of the electrostatic potential, ion density, ion currents, and equilibrium properties. Our results demonstrate that the incorporation of a charge distribution akin GJCs decreased anionic currents, favoring the transport of cationic species. Moreover, a thermodynamic characterization of ionic transport in these systems demonstrate the existence of a kinetic barrier that hinders anionic currents, reinforcing the role played by the internal arrangement of charges in GJCs. Overall, our results provide insights at the atomic scale on the effects of charge distributions over ionic transport, constituting a step forward into a better understanding of GJCs.

Modulation of Asymmetric Flux in Heterotypic Gap Junctions by Pore Shape, Particle Size and Charge

“…A lack of structural details of Cx isoforms is a major hurdle for accurate modeling at this stage. Simplified models implementing pore wall charges in in silico studies with Cx26 channels have been reported (Escalona et al, 2016). Such simplified application of pore electrostatics can be envisioned to study the role of different combinations of charges and in-pore charge-locations.…”

“…Structural details are a requisite for using existing computational approaches for studying membrane channels like ion channels (Allen et al, 1999; Corry et al, 2001; Chung et al, 2002; Vora et al, 2008) and porins (Schirmer and Phale, 1999; Im and Roux, 2002; Lee et al, 2011). Molecular modeling of Cx26 hemichannels (Kwon et al, 2011; Zonta et al, 2014) and gap junctions (Bennett et al, 2016; Escalona et al, 2016) was performed for studying their structure/function relations. Limitations and difficulties in deriving such structures pose a barrier to studying the structure and permeability of the whole range of gap junction channel types.…”

Peer Review #1 of "RIP-MD: a tool to study residue interaction networks in protein molecular dynamics (v0.1)"

“…GJCs are formed by the extracellular docking of two HCs, (Figure 2.A), where each HC is formed by six CXs monomers ( Figure 2.B). In this example, we studied a 20ns all-atom MD simulation of a complete GJC formed by the human CX26 [13]. This molecular system contains twelve identical CX monomers in total, each one comprising 226 AAs.…”

Carbenoxolone inhibits mechanical stress-induced osteogenic differentiation of mesenchymal stem cells by regulating p38 MAPK phosphorylation

“…GJs are composed of two adjacent hemichannels which anchor to each other, forming a hydrophilic channel ( 6 ) for intercellular communication via small molecules, such as inorganic ions (calcium and potassium), amino acids and glucose ( 7 , 8 ). GJs are dynamic structures, and a variety of factors are involved in regulating their opening and closing, such as intracellular pH, calcium ion (Ca 2+ ) concentration, and membrane potential ( 9 ). GJs have functions in cell metabolism and differentiation, transmission of nerve impulses and conduction of information, coordination of consistency between cellular activity, material transport, and electrical excitation conduction ( 10 ).…”