title: Induction of pseudo-periodic oscillation in voltage-gated sodium channel properties is dependent on the duration of prolonged depolarization.
abstract: 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 rNa(v)1.2a voltage-gated sodium channel alpha-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 beta1-subunit affected the time periods of oscillation (close to 22 s for alpha + beta1) 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 alpha-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.
authors.affiliation: Molecular Biophysics Unit, Indian Institute of Science, Bangalore-560012, India.
authors.forename: Sriparna
authors.initials: S
authors.lastname: Majumdar
authors.forename: Grant
authors.initials: G
authors.lastname: Foster
authors.forename: Sujit K
authors.initials: SK
authors.lastname: Sikdar
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004558:Electric Stimulation / Q000379:methods; D049452:Green Fluorescent Proteins; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D007700:Kinetics; D008164:Luminescent Proteins / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D008959:Models, Neurological; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D018408:Patch-Clamp Techniques / Q000379:methods; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection / Q000379:methods
chemical_list: D008164:Luminescent Proteins; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D049452:Green Fluorescent Proteins; D013779:Tetrodotoxin