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First published online on March 21, 2003.
 Copyright © 2003 by The Physiological Society
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Received January 9, 2003
Accepted after revision January 31, 2003

GTP-induced tetrodotoxin-resistant Na+ current regulates excitability in mouse and rat small diameter sensory neurones

M. D. Baker1*, Sonia Y. Chandra2, Yanning Ding2, Stephen G. Waxman3, and John N. Wood2

1 Molecular Nociception Group, Department of Biology, University College London, Gower Street, London WC1E 6BT, UK
2 Molecular Nociception Group, Department of Biology, Medawar Building, University College London, Gower Street, London WC1E 6BT, UK
3 Department of Neurology and PVA/EPVA Neuroscience Research Center, Yale University School of Medicine, New Haven, CT 06510, USA

* To whom correspondence should be addressed. E-mail: mark.baker{at}ucl.ac.uk.

Peripheral pain thresholds are regulated by the actions of inflammatory mediators. Some act through G-protein-coupled receptors on voltage-gated sodium channels. We have found that a low-threshold, persistent tetrodotoxin-resistant Na+ current, attributed to NaV1.9, is upregulated by GTP and its non-hydrolysable analogue GTP-{gamma}-S, but not by GDP. Inclusion of GTP-{gamma}-S (500 µM) in the internal solution led to an increase in maximal current amplitude of > 300 % within 5 min. In current clamp, upregulation of persistent current was associated with a more negative threshold for action potential induction (by 15-16 mV) assessed from a holding potential of -90 mV. This was not seen in neurones without the low-threshold current or with internal GDP (P < 0.001). In addition, persistent current upregulation depolarized neurones. At -60 mV, internal GTP-{gamma}-S led to the generation of spontaneous activity in initially silent neurones only when persistent current was upregulated. These findings suggest that regulation of the persistent current has important consequences for nociceptor excitability.




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