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

Authors :
Östman, Johan A. R.
Nassar, Mohammed A.
Wood, John N.
Baker, Mark D.
Source :
Journal of Physiology; Feb2008, Vol. 586 Issue 4, p1077-1087, 11p, 1 Diagram, 5 Graphs
Publication Year :
2008

Abstract

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<subscript>V</subscript>1.9 sodium channel. Here we describe the properties of a global knock-out of Na<subscript>V</subscript>1.9 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<superscript>+</superscript> current in Na<subscript>V</subscript>1.9-null neurones and the concomitant negative shift in voltage-threshold seen in wild-type and heterozygous neurones. Heterologous hNa<subscript>V</subscript>1.9 expression in Na<subscript>V</subscript>1.9 knock-out sensory neurones confirms that the human clone can restore the persistent Na<superscript>+</superscript> current. Taken together, these findings demonstrate that Na<subscript>V</subscript>1.9 underlies the G-protein pathway-regulated TTX-r persistent Na<superscript>+</superscript> current in small diameter sensory neurones that may drive spontaneous discharge in nociceptive nerve fibres during inflammation. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00223751
Volume :
586
Issue :
4
Database :
Complementary Index
Journal :
Journal of Physiology
Publication Type :
Academic Journal
Accession number :
29984998
Full Text :
https://doi.org/10.1113/jphysiol.2007.147942