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Stochastic 16-state model of voltage gating of gap-junction channels enclosing fast and slow gates.

ABSTRACT: Gap-junction (GJ) channels formed of connexin (Cx) proteins provide a direct pathway for electrical and metabolic cell-cell interaction. Each hemichannel in the GJ channel contains fast and slow gates that are sensitive to transjunctional voltage (Vj). We developed a stochastic 16-state model (S16SM) that details the operation of two fast and two slow gates in series to describe the gating properties of homotypic and heterotypic GJ channels. The operation of each gate depends on the fraction of Vj that falls across the gate (VG), which varies depending on the states of three other gates in series, as well as on parameters of the fast and slow gates characterizing 1), the steepness of each gate's open probability on VG; 2), the voltage at which the open probability of each gate equals 0.5; 3), the gating polarity; and 4), the unitary conductances of the gates and their rectification depending on VG. S16SM allows for the simulation of junctional current dynamics and the dependence of steady-state junctional conductance (gj,ss) on Vj. We combined global coordinate optimization algorithms with S16SM to evaluate the gating parameters of fast and slow gates from experimentally measured gj,ss-Vj dependencies in cells expressing different Cx isoforms and forming homotypic and/or heterotypic GJ channels.

SUBMITTER: Paulauskas N

PROVIDER: S-EPMC3368129 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Publications

Stochastic 16-state model of voltage gating of gap-junction channels enclosing fast and slow gates.

Paulauskas Nerijus N Pranevicius Henrikas H Mockus Jonas J Bukauskas Feliksas F FF

Biophysical journal 20120605 11

Gap-junction (GJ) channels formed of connexin (Cx) proteins provide a direct pathway for electrical and metabolic cell-cell interaction. Each hemichannel in the GJ channel contains fast and slow gates that are sensitive to transjunctional voltage (Vj). We developed a stochastic 16-state model (S16SM) that details the operation of two fast and two slow gates in series to describe the gating properties of homotypic and heterotypic GJ channels. The operation of each gate depends on the fraction of ...[more]

PMID: 22713562

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Project description:Connexins, a family of membrane proteins, form gap junction (GJ) channels that provide a direct pathway for electrical and metabolic signaling between cells. We developed a stochastic four-state model describing gating properties of homotypic and heterotypic GJ channels each composed of two hemichannels (connexons). GJ channel contain two "fast" gates (one per hemichannel) oriented opposite in respect to applied transjunctional voltage (V(j)). The model uses a formal scheme of peace-linear aggregate and accounts for voltage distribution inside the pore of the channel depending on the state, unitary conductances and gating properties of each hemichannel. We assume that each hemichannel can be in the open state with conductance gamma(h,o) and in the residual state with conductance gamma(h,res), and that both gamma(h,o) and gamma(h,res) rectifies. Gates can exhibit the same or different gating polarities. Gating of each hemichannel is determined by the fraction of V(j) that falls across the hemichannel, and takes into account contingent gating when gating of one hemichannel depends on the state of apposed hemichannel. At the single-channel level, the model revealed the relationship between unitary conductances of hemichannels and GJ channels and how this relationship is affected by gamma(h,o) and gamma(h,res) rectification. Simulation of junctions containing up to several thousands of homotypic or heterotypic GJs has been used to reproduce experimentally measured macroscopic junctional current and V(j)-dependent gating of GJs formed from different connexin isoforms. V(j)-gating was simulated by imitating several frequently used experimental protocols: 1), consecutive V(j) steps rising in amplitude, 2), slowly rising V(j) ramps, and 3), series of V(j) steps of high frequency. The model was used to predict V(j)-gating of heterotypic GJs from characteristics of corresponding homotypic channels. The model allowed us to identify the parameters of V(j)-gates under which small changes in the difference of holding potentials between cells forming heterotypic junctions effectively modulates cell-to-cell signaling from bidirectional to unidirectional. The proposed model can also be used to simulate gating properties of unapposed hemichannels.

Dataset Information

Stochastic 16-state model of voltage gating of gap-junction channels enclosing fast and slow gates.

Publications

Stochastic 16-state model of voltage gating of gap-junction channels enclosing fast and slow gates.

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