Persistent Na+ current

In addition to inhibiting fast voltage-dependent Na+ currents, many anticonvulsants also suppress persistent Na+ currents, in some cases even more efficiently. This mechanism may also be important in the anticonvulsant action of these substances because persistent Na+ currents are thought to give rise to high frequency burst discharges in some neurons. 

Alzheimer C, Schwindt PC, Crill WE 1993a Modal gating of Na channels as a mechanism of persistent Na current in pyramidal neurons from rat and cat sensorimotor cortex. J Neurosci 13 660-673... 

Cummins An important factor in understanding inactivation and the generation of persistent currents may be subtle differences between the skeletal muscle and neuronal channels or isoforms. Patlak Ortiz (1986) found that noninactivating or persistent Na currents in skeletal muscle cells were very small, whereas in the squid axons persistent Na+ currents are much larger. There seem to be subtle but important differences between the different isoforms. There may be differences in cooperativity. All of this has to be worked out very carefully. 

Segal The other possibility is that the persistent Na current is the most important determinant of excitability. The excitability increase from a doubling of the persistent Na current could outweigh a 30% decrease in channel number. 

Catterall In the hippocampal neurons there is an obvious change in persistent Na current in the j52 knockouts. 

All patches with Na+ channels had both early and late channel openings, corresponding to peak and persistent Na+ currents. The persistent Na current was typically 0.5% of the peak current. The Na channel openings included both the brief late openings and the burst openings described in other neuronal (Alzheimer et al 1993) and muscle cells (Patlak Ortiz 1986), openings that are believed to represent different kinetic states of the same channel molecule (Moorman et al 1990). The burst openings were seen in far less than 1% of pulses, and in some patches were not seen at all. 

From these experiments it appears that the inward current that drives the neuronal bursts that underlie the ictal activity is a persistent Na current. We were not able to get large numbers of experiments in which whole cell activity could be correlated with single channel events from the same neuron. Therefore it is not clear whether the endogenous bursting in t he neurons with ictal activity is due to an increase in overall persistent Na current, a specific increase in burst openings, or a decrease in countervailing K currents. 

In summary, it appears that the persistent Na current has a major role in driving the ictal activity that underlies seizures. Although mutations of Na channels are likely to underlie only a small fraction of cases of epilepsy, it is likely that the persistent Na current represents a final common pathway in many cases of epilepsy. A good strategy for developing new anticonvulsants with fewer side effects may be to search for drugs that more selectively block the persistent Na current at depolarized voltages. 

Segal The plateau outlasted the spiking about half the time. This impressed us very much for the reason you mentioned — this suggested an equal balance between Na currents and K currents that we knew could be large. This is what led us to consider the possibility that persistent Na currents were large, something that seemed hard to believe 10 years ago. 

Chao TI, Alzheimer C 1995 Effects of phenytoin on the persistent Na current of mammalian CNS neurons. NeuroReport 6 1778-1780... 

Bean I can echo Rodolfo Llinas ideas on this, which I think are insightful. A primary result from persistent Na+ current is to induce overall oscillatory activity in the CNS. This is crucial for the function of the nervous system in some way we still don t understand. A cost of this is the possibility of going into a less well controlled oscillatory activity. The normal oscillatory activity that you see reflected in the normal EEG may well reflect the activity of the persistent Na + currents in some cell types. 

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