Voltage Dependence of Sodium Channel Inactivation In The Squid Giant Axon

An attempt is made to model sodium channel inactivation based upon real physical processes. The principle involved, which is supported by calculation and by direct appeal to experimental results, is that the gating dipole reversal or gating charge transfer that occurs when the channel is activated, markedly modulates the electrical properties of charged groups at the channel ends. Four examples of possible mechanisms that lead to channel inactivation are described. The simple four-state model that results is able to predict: ( а ) the steep voltage dependence of the equilibrium inactivation characteristic without the presence of any appreciable displacement current associated with inactivation; ( b ) the negative shift in membrane voltage of the equilibrium inactivation characteristic relative to the activation characteristic; ( c ) the bell-shaped dependence of inactivation time constant on membrane voltage; ( d ) the similarity of the membrane voltage dependence of the time constant of recovery from inactivation, to that of inactivation itself. A brief discussion of a model for sodium channel activation based upon the same physical principle is included.

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Sodium Channel Inactivation Is Altered by Substitution of Voltage Sensor Positive Charges

The Journal of General Physiology ◽

10.1085/jgp.110.4.403 ◽

1997 ◽

Vol 110 (4) ◽

pp. 403-413 ◽

Cited By ~ 69

Author(s):

Kris J. Kontis ◽

Alan L. Goldin

Keyword(s):

Sodium Channel ◽

Voltage Dependence ◽

Voltage Sensor ◽

Voltage Sensitivity ◽

Slow Inactivation ◽

Fast Inactivation ◽

Α Subunit ◽

Channel Inactivation ◽

Sodium Channel Inactivation ◽

Domain I

The role of the voltage sensor positive charges in fast and slow inactivation of the rat brain IIA sodium channel was investigated by mutating the second and fourth conserved positive charges in the S4 segments of all four homologous domains. Both charge-neutralizing mutations (by glutamine substitution) and charge-conserving mutations were constructed in a cDNA encoding the sodium channel α subunit. To determine if fast inactivation altered the effects of the mutations on slow inactivation, the mutations were also constructed in a channel that had fast inactivation removed by the incorporation of the IFMQ3 mutation in the III–IV linker (West, J.W., D.E. Patton, T. Scheuer, Y. Wang, A.L. Goldin, and W.A. Catterall. 1992. Proc. Natl. Acad. Sci. USA. 89:10910– 10914). Most of the mutations shifted the v1/2 of fast inactivation in the negative direction, with the largest effects resulting from mutations in domains I and II. These shifts were in the opposite direction compared with those observed for activation. The effects of the mutations on slow inactivation depended on whether fast inactivation was intact or not. When fast inactivation was eliminated, most of the mutations resulted in positive shifts in the v1/2 of slow inactivation. The largest effects again resulted from mutations in domains I and II. When fast inactivation was intact, the mutations in domains II and III resulted in negative shifts in the v1/2 of slow inactivation. Neutralization of the fourth charge in domain I or II resulted in the appearance of a second component in the voltage dependence of slow inactivation that was only observable when fast inactivation was intact. These results suggest the S4 regions of all four domains of the sodium channel are involved in the voltage dependence of inactivation, but to varying extents. Fast inactivation is not strictly coupled to activation, but it derives some independent voltage sensitivity from the charges in the S4 domains. Finally, there is an interaction between the fast and slow inactivation processes.

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