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¹ Centre for Neuroscience, Institute of Cell and Molecular Science, Queen Mary University of London, Newark Street, London E1 2AT, UK
² Molecular Nociception, Department of Biology, University College London, Gower Street, London WC1E 6BT, UK

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--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.

(Received 8 November 2007; accepted after revision 14 December 2007; first published online 20 December 2007)
Corresponding author M. Baker: Centre for Neuroscience, Institute of Cell and Molecular Science, Queen Mary University of London, Newark Street, London E1 2AT, UK. Email: m.d.baker{at}qmul.ac.uk

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