Role of tetrodotoxin-resistant Na+ current slow inactivation in adaptation of action potential firing in small-diameter dorsal root ganglion neurons.
When acutely dissociated small-diameter dorsal root ganglion (DRG) neurons were stimulated with repeated current injections or prolonged application of capsaicin, their action potential firing quickly adapted. Because TTX-resistant (TTX-R) sodium current in these presumptive nociceptors generates a large fraction of depolarizing current during the action potential, we examined the possible role of inactivation of TTX-R sodium channels in producing adaptation. Under voltage clamp, TTX-R current elicited by short depolarizations showed strong use dependence at frequencies as low as 1 Hz, although recovery from fast inactivation was complete in approximately 10-30 msec. This use-dependent reduction was the result of the entry of TTX-R sodium channels into slow inactivated states. Slow inactivation was more effectively produced by steady depolarization than by cycling channels through open states. Slow inactivation was steeply voltage dependent, with a Boltzmann slope factor of 5 mV, a midpoint near -45 mV (5 sec conditioning pulses), and completeness of approximately 93% positive to -20 mV. The time constant for entry (approximately 200 msec) was independent of voltage from -20 mV to +60 mV, whereas recovery kinetics were moderately voltage dependent (time constant, approximately 1.5 sec at -60 mV and approximately 0.5 sec at -100 mV). Using a prerecorded current-clamp response to capsaicin as a voltage-clamp command waveform, we found that adaptation of firing occurred with a time course similar to that of development of slow inactivation. Thus, slow inactivation of the TTX-R sodium current limits the duration of small DRG cell firing in response to maintained stimuli and may contribute to cross desensitization between chemical and electrical stimuli.
Blair
Nathaniel T
NT
Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Bean
Bruce P
BP
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000222:Adaptation, Physiological / Q000187:drug effects; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D048429:Cell Size; D002478:Cells, Cultured; D005727:Ganglia, Spinal / Q000166:cytology*; D007700:Kinetics; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D051381:Rats; D020318:Rats, Long-Evans; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000145:classification / Q000187:drug effects / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology*
D015222:Sodium Channels; D013779:Tetrodotoxin; D012964:Sodium; D002211:Capsaicin