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GTP up-regulated persistent Na+ current and enhanced nociceptor excitability require NaV1.9
Johan A R Ostman1, Mohammed A Nassar, John N Wood
1Centre for Neuroscience, Institute of Cell and Molecular Science, Queen Mary University of London, Newark Street, London E1 2AT, UK.
The Journal of Physiology
|December 22, 2007
Summary
The Na(V)1.9 sodium channel is crucial for persistent sodium currents in sensory neurons, influencing pain signaling. Knocking out Na(V)1.9 eliminates these currents, impacting inflammatory pain pathways.
Area of Science:
- Neuroscience
- Molecular Biology
- Pain Research
Background:
- Persistent tetrodotoxin-resistant (TTX-r) sodium currents, linked to the Na(V)1.9 channel, are implicated in inflammatory pain.
- These currents are modulated by intracellular GTP and peripheral inflammatory mediators, lowering pain thresholds.
Purpose of the Study:
- To investigate the role of the Na(V)1.9 sodium channel in TTX-r persistent currents.
- To determine if Na(V)1.9 is the primary target for G-protein pathway regulation in sensory neurons.
Main Methods:
- Generation of a global Na(V)1.9 knock-out mouse model by genetic manipulation of the SCN11A gene.
- Electrophysiological recordings from sensory neurons of wild-type, heterozygous, and knock-out mice.
- Heterologous expression of human Na(V)1.9 in knock-out sensory neurons.
Main Results:
- Loss of Na(V)1.9 function in knock-out neurons abolished TTX-r persistent sodium currents.
- GTP-gamma-S failed to up-regulate persistent currents or shift voltage thresholds in Na(V)1.9-null neurons.
- Re-expression of human Na(V)1.9 in knock-out neurons restored the persistent sodium current.
Conclusions:
- Na(V)1.9 is essential for the G-protein regulated TTX-r persistent sodium current in small sensory neurons.
- This current likely contributes to spontaneous discharge in nociceptive fibers during inflammation.
- Na(V)1.9 represents a potential therapeutic target for inflammatory pain.
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