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First published online on December 20, 2007.
 Copyright © 2007 by The Physiological Society
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jphysiol.2007.147942v1
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Received November 8, 2007
Revised November 28, 2007
Accepted after revision December 14, 2007

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

Johan AR Östman1, Mohammed A Nassar2, John N Wood2, and Mark D Baker1*

1 Queen Mary University of London
2 University College London

* To whom correspondence should be addressed. E-mail: m.d.baker{at}qmul.ac.uk.

Persistent tetrodotoxin-resistant (TTX-r) sodium currents upregulated by intracellular GTP have been invoked as the site of action of peripheral inflammatory mediators that lower pain thresholds, and ascribed to the NaV1.9 sodium channel. Here we describe the properties of a global knock-out of NaV1.9 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-{gamma}-S did not cause an up-regulation of persistent Na+ current in NaV1.9-null neurones and the concomitant negative-shift in voltage-threshold seen in wild-type and heterozygous neurones. Heterologous hNaV1.9 expression in NaV1.9 knock-out sensory neurones confirms that the human clone can restore the persistent Na+ current. Taken together, these findings demonstrate that NaV1.9 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.


Key words: Pain • Sensory neurons • Sodium (Na+) channel


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