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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.

SUBMITTER: Escalona Y

PROVIDER: S-EPMC4919569 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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

Escalona Yerko Y Garate Jose A JA Araya-Secchi Raul R Huynh Tien T Zhou Ruhong R Perez-Acle Tomas T

Biophysical journal 20160601 12

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-mem ...[more]

PMID: 27332126

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Project description:Human immunodeficiency virus-1 (HIV-1) infection compromises the central nervous system (CNS) in a significant number of infected individuals, resulting in neurological dysfunction that ranges from minor cognitive deficits to frank dementia. While macrophages/microglia are the predominant CNS cells infected by HIV, our laboratory and others have shown that HIV-infected astrocytes, although present in relatively low numbers with minimal to undetectable viral replication, play key role in NeuroAIDS pathogenesis. Our laboratory has identified that HIV "hijacks" connexin (Cx) containing channels, such as gap junctions (GJs) and hemichannels (HCs), to spread toxicity and apoptosis to uninfected cells even in the absence of active viral replication. In this study, using a murine model with an astrocyte-directed deletion of Cx43 gene (hGFAP-cre Cx43fl/fl) and control Cx43fl/fl mice, we examined whether few HIV-infected human astrocytoma cells (U87-CD4-CCR5), microinjected into the mouse cortex, can spread toxicity and apoptosis through GJ-mediated mechanisms, into the mouse cells, which are resistant to HIV infection. In the control Cx43fl/fl mice, microinjection of HIV-infected U87-CD4-CCR5 cells led to apoptosis in 84.28 ± 6.38% of mouse brain cells around the site of microinjection, whereas hGFAP-cre Cx43fl/fl mice exhibited minimal apoptosis (2.78 ± 1.55%). However, simultaneous injection of GJ blocker, 18?-glycyrrhetinic acid, and Cx43 blocking peptide along with microinjection of HIV-infected cells prevented apoptosis in Cx43fl/fl mice, demonstrating the Cx43 is essential for HIV-induced bystander toxicity. In conclusion, our findings demonstrate that Cx43 expression, and formation of GJs is essential for bystander apoptosis during HIV infection. These findings reveal novel potential therapeutic targets to reduce astrocyte-mediated bystander toxicity in HIV-infected individuals because despite low to undetectable viral replication in the CNS, Cx channels hijacked by HIV amplify viral neuropathogenesis.

Dataset Information

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

Publications

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

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