Sodium channel slow inactivation interferes with open channel block

Abstract

Mutations in the voltage-gated sodium channel Nav1.7 are linked to inherited pain syndromes such as erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). PEPD mutations impair Nav1.7 fast inactivation and increase persistent currents. PEPD mutations also increase resurgent currents, which involve the voltage-dependent release of an open channel blocker. In contrast, IEM mutations, whenever tested, leave resurgent currents unchanged. Accordingly, the IEM deletion mutation L955 (ΔL955) fails to produce resurgent currents despite enhanced persistent currents, which have hitherto been considered a prerequisite for resurgent currents. Additionally, ΔL955 exhibits a prominent enhancement of slow inactivation (SI). We introduced mutations into Nav1.7 and Nav1.6 that either enhance or impair SI in order to investigate their effects on resurgent currents. Our results show that enhanced SI is accompanied by impaired resurgent currents, which suggests that SI may interfere with open-channel block.

Conservation of alternative splicing in sodium channels reveals evolutionary focus on release from inactivation and structural insights into gating

“…Indeed, although our holding potential of −80 mV is in the range of physiological potentials where neurons may rest, this potential is within a range where a significant portion of Nav1.7 will be in slow inactivated states (Hampl et al . ). However, for all three channels, the difference in channel availability was evident after a single step and was sustained for the entire train, with the A variants remaining less available than the N variants ( P < 0.01 for all three channels, two‐way ANOVA).…”

The role of Nav1.7 in human nociceptors: insights from human induced pluripotent stem cell–derived sensory neurons of erythromelalgia patients

“…This corresponds well with published activation V 1/2 values for these Na V channels (Na V 1.1, 6,8 Na V 1.2, 8,22,44 Na V 1.3, 8,10 Na V 1.6, 4,8,36 and Na V 1.9 26,41 ), all of which were reported to be more hyperpolarized compared with Na V 1.7. 10,11,18,24,40,43…”

Pain relief in a neuropathy patient by lacosamide: Proof of principle of clinical translation from patient-specific iPS cell-derived nociceptors

“…We therefore tested patient derived-sensory neurons for their response to lacosamide, an FDA approved compound known to block voltage-gated sodium channels. We used 500 μM, as this concentration was previously used in in vitro studies [26], and 50 μM, which corresponds to the plasma concentration in patients [25]. The concentration at the side of action is unknown and beyond the reach of most experiments.…”