GTP up-regulated persistent Na+ current and enhanced nociceptor excitability require NaV1.9.

Persistent tetrodotoxin-resistant (TTX-r) sodium currents up-regulated by intracellular GTP have been invoked as the site of action of peripheral inflammatory mediators that lower pain thresholds, and ascribed to the Na_V1.9 sodium channel. Here we describe the properties of a global knock-out of Na_V1.9 produced by replacing exons 4 and 5 in SCN11A with a neomycin resistance cassette, deleting the domain 1 voltage sensor and introducing a frameshift mutation. Recordings from small (< 25 μm apparent diameter) sensory neurones indicated that channel loss eliminates a TTX-r persistent current. Intracellular dialysis of GTP-γ-S did not cause an up-regulation of persistent Na⁺ current in Na_V1.9-null neurones and the concomitant negative shift in voltage-threshold seen in wild-type and heterozygous neurones. Heterologous hNa_V1.9 expression in Na_V1.9 knock-out sensory neurones confirms that the human clone can restore the persistent Na⁺ current. Taken together, these findings demonstrate that Na_V1.9 underlies the G-protein pathway-regulated TTX-r persistent Na⁺ current in small diameter sensory neurones that may drive spontaneous discharge in nociceptive nerve fibres during inflammation. [ABSTRACT FROM AUTHOR]