GTP-induced tetrodotoxin-resistant Na+ current regulates excitability in mouse and rat small diameter sensory neurones.
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 microM) 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.
Baker
Mark D
MD
Molecular Nociception Group, Department of Biology, Medawar Building, University College London, Gower Street, UK. mark.baker@ucl.ac.uk
Chandra
Sonia Y
SY
Ding
Yanning
Y
Waxman
Stephen G
SG
Wood
John N
JN
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000465:Algorithms; D000818:Animals; D004594:Electrophysiology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000502:physiology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D006160:Guanosine Triphosphate / Q000494:pharmacology*; D051379:Mice; D062558:NAV1.9 Voltage-Gated Sodium Channel; D009475:Neurons, Afferent / Q000187:drug effects* / Q000648:ultrastructure; D009479:Neuropeptides / Q000819:agonists / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D047428:Protein Kinase Inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D062687:Sodium Channel Agonists; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D062558:NAV1.9 Voltage-Gated Sodium Channel; D009479:Neuropeptides; D047428:Protein Kinase Inhibitors; C491885:Scn11a protein, mouse; C113705:Scn11a protein, rat; D062687:Sodium Channel Agonists; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D013779:Tetrodotoxin; D006160:Guanosine Triphosphate; D019204:GTP-Binding Proteins