Protein kinase C-dependent modulation of Na+ currents increases the excitability of rat neocortical pyramidal neurones

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Abstract

  • 1The effect of the protein kinase C (PKC) activator 1-oleoyl-2-acetyl-sn-glycerol (OAG) on TTX-sensitive Na+ currents in neocortical pyramidal neurones was evaluated using voltage-clamp and intracellular current-clamp recordings.
  • 2In pyramid-shaped dissociated neurones, the addition of OAG to the superfusing medium consistently led to a 30 % reduction in the maximal peak amplitude of the transient sodium current (INa,T) evoked from a holding potential of −70 mV. We attributed this inhibitory effect to a significant negative shift of the voltage dependence of steady-state channel inactivation (of approximately 14 mV). The inhibitory effect was completely prevented by hyperpolarising prepulses to potentials that were more negative than −80 mV. A small but significant leftward shift of INa,T activation was also observed, resulting in a slight increase of the currents evoked by test pulses at potentials more negative then −35 mV.
  • 3In the presence of OAG, the activation of the persistent fraction of the Na+ current (INa,P) evoked by means of slow ramp depolarisations was consistently shifted in the negative direction by 3.9 ± 0.5 mV, while the peak amplitude of the current was unaffected.
  • 4In slice experiments, the OAG perfusion enhanced a subthreshold depolarising rectification affecting the membrane response to the injection of positive current pulses, and thus led the neurones to fire in response to significantly lower depolarising stimuli than those needed under control conditions. This effect was attributed to an OAG-induced enhancement of INa,P, since it was observed in the same range of potentials over which INa,P activates and was completely abolished by TTX.
  • 5The qualitative firing characteristics of both the intrinsically bursting and regular spiking neurones were unaffected when OAG was added to the physiological perfusing medium, but their firing frequency increased in response to slight suprathreshold depolarisations.
  • 6The obtained results suggest that physiopathological events working through PKC activation can increase neuronal excitability by directly amplifying the INa,P-dependent subthreshold depolarisation, and that this facilitating effect may override the expected reduction in neuronal excitability deriving from OAG-induced inhibition of the maximal INa,T peak amplitude.

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