Induction of pseudo-periodic oscillation in voltage-gated sodium channel properties is dependent on the duration of prolonged depolarization

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The neuronal voltage-gated sodium channels play a vital role in the action potential waveform shaping and propagation. Here, we report the effects of prolonged depolarization (1–160 s) on the detailed kinetics of activation, fast inactivation and recovery from slow inactivation in the rNav1.2a voltage-gated sodium channel α-subunit expressed in Chinese hamster ovary (CHO) cells. Wavelet analysis revealed that the duration and amplitude of a prolonged sustained depolarization altered all the steady state and kinetic parameters of the channel in a pseudo-oscillatory fashion with time-variable period and amplitude, often superimposed on a linear trend. The half steady state activation potential showed a reversible depolarizing shift of 5–10 mV with duration of prolonged depolarization, while half steady state inactivation potential showed a hyperpolarizing shift of 43–55 mV. The time periods for most of the parameters relating to activation and fast and slow inactivation, lie close to 28–30 s, suggesting coupling of these kinetic processes through an oscillatory mechanism. Co-expression of the β1-subunit affected the time periods of oscillation (close to 22 s for α + β1) in steady state activation parameters. Application of a pulse protocol that mimicked paroxysmal depolarizing shift (PDS), a kind of depolarization seen in epileptic discharges, instead of a sustained depolarization, also caused oscillatory behaviour in the rNav1.2a α-subunit. This inherent pseudo-oscillatory mechanism may regulate excitability of the neurons, account for the epileptic discharges and subthreshold membrane potential oscillation and offer a molecular memory mechanism intrinsic to the neurons, independent of synaptic plasticity.

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