Sodium channels expressed in nociceptors contribute distinctly to action potential subthreshold phase, upstroke and shoulder

Abstract

Voltage-gated sodium channels (VGSC) in the peripheral nervous system shape action potentials (AP) and thereby support the detection of sensory stimuli. Most of the nine mammalian VGSC subtypes are expressed in nociceptors, but predominantly, three are linked to several human pain syndromes: while Na_v1.7 is suggested to be a (sub-)threshold channel, Na_v1.8 is thought to support the fast AP upstroke. Na_v1.9, as it produces large persistent currents, is attributed a role in determining the resting membrane potential.

We characterized gating of Na_v1.1-Na_v1.3 and Na_v1.5-Na_v1.9 in manual patch clamp with focus on the AP subthreshold depolarization phase. Na_v1.9 exhibited the most hyperpolarized activation while its fast inactivation resembled the depolarized inactivation of Na_v1.8. For some VGSCs (e.g., Na_v1.1 and Na_v1.2), a positive correlation between ramp current and window current was detected.

Using a modified Hodgkin-Huxley model which accounts for the time needed for inactivation to occur, we used the acquired data to simulate two nociceptive nerve fiber types (an Aδ-and a mechano-insensitive C-nociceptor) containing VGSC conductances according to published human RNAseq data. Our simulations suggest that Na_v1.9 is supporting both the AP upstroke and its shoulder. A reduced threshold for AP generation was induced by enhancing Na_v1.7 conductivity or shifting its activation to more hyperpolarized potentials, as observed in Na_v1.7-related pain disorders.

Here, we provide a comprehensive, comparative functional characterization of VGSCs relevant in nociception and describe their gating with Hodgkin-Huxley-like models, which can serve as a tool to study their specific contributions to AP shape and sodium channel-related diseases.