Gating and modulation of presumptive NaV1.9 channels in enteric and spinal sensory neurons.
The NaV1.9 subunit is expressed in nociceptive dorsal root ganglion (DRG) neurons and sensory myenteric neurons in which it generates 'persistent' tetrodotoxin-resistant (TTX-R) Na+ currents of yet unknown physiological functions. Here, we have analyzed these currents in details by combining single-channel and whole-cell recordings from cultured rat DRG and myenteric neurons. Comparison of single-channel with whole-cell data indicates that recording using internal CsCl best reflects the basic electrical features of NaV1.9 currents. Inclusion of fluoride in the pipette solution caused a negative shift in the activation and inactivation gates of NaV1.9 but not NaV1.8. Fluoride acts by promoting entry of NaV1.9 channels into a preopen closed state, which causes a strong bias towards opening and enhances the ability of sensory neurons to sustain spiking. Thus, the modulation of the resting-closed states of NaV1.9 channels strongly influences nociceptor excitability and may provide a mechanism by which inflammatory mediators alter pain threshold.
Coste
Bertrand
B
Intégration des Informations Sensorielles, CNRS, UMR 6150, Faculté de Médecine, IFR Jean Roche, 13916 Marseille 20, France.
Osorio
Nancy
N
Padilla
Françoise
F
Crest
Marcel
M
Delmas
Patrick
P
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D002586:Cesium / Q000494:pharmacology; D002712:Chlorides / Q000494:pharmacology; D005459:Fluorides / Q000494:pharmacology; D005725:Ganglia, Autonomic / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009197:Myenteric Plexus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D062558:NAV1.9 Voltage-Gated Sodium Channel; D009475:Neurons, Afferent / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009479:Neuropeptides / Q000187:drug effects / Q000378:metabolism*; D010146:Pain / Q000378:metabolism / Q000503:physiopathology; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism*
D002712:Chlorides; D018836:Inflammation Mediators; D062558:NAV1.9 Voltage-Gated Sodium Channel; D009479:Neuropeptides; C113705:Scn11a protein, rat; D015222:Sodium Channels; D002586:Cesium; C028019:cesium chloride; D005459:Fluorides