Regulating neuronal excitability: The role of S -palmitoylation in Na V 1.7 activity and voltage sensitivity.

S -palmitoylation, a reversible lipid post-translational modification, regulates the functions of numerous proteins. Voltage-gated sodium channels (Na V s), pivotal in action potential generation and propagation within cardiac cells and sensory neurons, can be directly or indirectly modulated by S -palmitoylation, impacting channel trafficking and function. However, the role of S -palmitoylation in modulating Na V 1.7, a significant contributor to pain pathophysiology, has remained unexplored. Here, we addressed this knowledge gap by investigating if S -palmitoylation influences Na V 1.7 channel function. Acyl-biotin exchange assays demonstrated that heterologously expressed Na V 1.7 channels are modified by S -palmitoylation. Blocking S -palmitoylation with 2-bromopalmitate resulted in reduced Na V 1.7 current density and hyperpolarized steady-state inactivation. We identified two S -palmitoylation sites within Na V 1.7, both located in the second intracellular loop, which regulated different properties of the channel. Specifically, S -palmitoylation of cysteine 1126 enhanced Na V 1.7 current density, while S -palmitoylation of cysteine 1152 modulated voltage-dependent inactivation. Blocking S -palmitoylation altered excitability of rat dorsal root ganglion neurons. Lastly, in human sensory neurons, Na V 1.7 undergoes S -palmitoylation, and the attenuation of this post-translational modification results in alterations in the voltage-dependence of activation, leading to decreased neuronal excitability. Our data show, for the first time, that S -palmitoylation affects Na V 1.7 channels, exerting regulatory control over their activity and, consequently, impacting rodent and human sensory neuron excitability. These findings provide a foundation for future pharmacological studies, potentially uncovering novel therapeutic avenues in the modulation of S -palmitoylation for Na V 1.7 channels.