Cellular mechanisms regulating the upregulation of Na_V1.9, a TTX-resistant Na channel, in mouse dorsal root ganglion neurons

Abstract

Sensory neurons in dorsal root ganglion (DRG) express two kinds of tetrodotoxin resistant isoforms of the voltage-gated sodium channel, Na_V1.8 (SNS) and Na_V1.9 (NaN). These tetrodotoxin-resistant isoforms play key roles in pathophysiology of chronic pain. Of special interest is Na_V1.9, which is preferentially expressed in small DRG neurons. Na_V1.9 mediates a persistent sodium current, which shows an extremely slow time course distinct from the sodium current mediated by Na_V1.8. Previously, we reported the unique properties of the sodium current mediated by Na_V1.9 (I_{TTX-R/persistent}) in neurons from Na_V1.8-null mutant mice, i.e., I_{TTX-R/persistent} recorded under whole-cell patch-clamp condition showed an explosive up-regulation of the peak amplitude of the current (“kindling” of I_{TTX-R/persistent}) during recording. However, the mechanism underlying the kindling of I_{TTX-R/persistent} is still unclear. Intracellular ATP (3 mM) and GTP (500 μM) significantly suppressed the kindling of I_{TTX-R/persistent}. The effect of ATP was more potent than the effect of GTP. In these cases, the shift of the steady-state inactivation was not observed. A PKC activator, PMA (10 nM) also inhibited the kindling of I_{TTX-R/persistent}. In the presence of a PKC inhibitor, Calphostin C, the effect of PMA was not observed. In addition, PMA shifted the steady-state inactivation. These results suggest that the functional expression of I_{TTX-R/persistent} may be strongly affected by a change in intracellular conditions. [Jpn J Physiol 55 Suppl:S129 (2005)]