Fig. 7.
In compartmental simulations, rightward shift in voltage dependence of slow inactivation, equivalent to one produced by TNF-α, leads to increase in AP firing rate. A: a Markovian state model for TTX-r sodium channel represents two parallel planes: the first, a classic Hodgkin-Huxley like kinetic scheme with fast voltage-dependent transition; and the second, describing the slow inactivation states with much slower kinetics (see materials and methods). O denotes the open state; C denotes the closed states; IC and SC represent the fast and slow inactivation states, respectively; and SIC is the state in which the channel is inactivated by both slow and fast inactivation mechanisms. Activation occurs with the independent movement of gates, with voltage-dependent transitions between the multiple closed states. B: responses of simulated neuron to 2,000-ms hyperpolarizing and depolarizing suprathreshold current steps without (left) and with (right) 3.32-mV rightward shift in the voltage dependence of slow inactivation of slow Nav 1.8 channels (see materials and methods). A 3.32-mV shift was used to match the shift in voltage dependence in slow inactivation produced by TNF-α (Fig. 6 and Table 2). Note the increase in AP firing following the same stimuli (shown below) when rightward shift is applied. C: f–I curves calculated with (black circles) and without (gray squares) a 3.32-mV rightward shift in the voltage dependence of slow inactivation of Nav 1.8 channels, expressed as spike frequency evoked by suprathreshold stimulus and plotted against stimuli intensity normalized to rheobase. Note the significantly increased spike frequency and increase in slope (m) of the f–I curve following the shift. D: rightward shift of 3.32 mV in voltage dependence of slow inactivation in simulated neuron produced increased firing rate in response to 1.5-s-long depolarizing current ramps (333 pA/s, shown below). E and F: histograms plotting the spike count (E) and the maximal velocity (dV/dt)max of the upstroke of the AP (F) with (black) and without (gray) 3.32-mV depolarizing shift in the voltage dependence of slow inactivation of Nav 1.8 channels.