Regulation/modulation of sensory neuron sodium channels

The pseudounipolar sensory neurons of the dorsal root ganglia (DRG) give rise to peripheral branches that convert thermal, mechanical, and chemical stimuli into electrical signals that are transmitted via central branches to the spinal cord. These neurons express unique combinations of tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) Na⁺ channels that contribute to the resting membrane potential, action potential threshold, and regulate neuronal firing frequency. The small-diameter neurons (<25 μm) isolated from the DRG represent the cell bodies of C-fiber nociceptors that express both TTX-S and TTX-R Na+ currents. The large-diameter neurons (>35 μm) are typically  low-threshold A-fibers that predominately express TTX-S Na⁺ currents. Peripheral nerve damage, inflammation, and metabolic diseases alter the expression and function of these Na⁺ channels leading to increases in neuronal excitability and pain. The Na⁺ channels expressed in these neurons are the target of intracellular signaling cascades that regulate the trafficking, cell surface expression, and gating properties of these channels. Post-translational regulation of Na⁺ channels by protein kinases (PKA, PKC, MAPK) alter the expression and function of the channels. Injury-induced changes in these signaling pathways have been linked to sensory neuron hyperexcitability and pain. This review examines the signaling pathways and regulatory mechanisms that modulate the voltage-gated Na⁺ channels of sensory neurons.