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The Journal of Neuroscience, April 1, 2003, 23(7):2715

Selective Expression of a Persistent Tetrodotoxin-Resistant Na⁺ Current and Na_V1.9 Subunit in Myenteric Sensory Neurons

François Rugiero¹, Mohini Mistry², Dominique Sage¹, Joel A. Black^{3, 4}, Stephen G. Waxman^{3, 4}, Marcel Crest¹, Nadine Clerc¹, Patrick Delmas¹, and Maurice Gola¹

¹ Intégration des Informations Sensorielles, Unite Mixte de Recherche 6150, Centre National de la Recherche Scientifique, 13916 Marseille, France, ² Wellcome Laboratory for Molecular Pharmacology, Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom, ³ Department of Neurology and Paralyzed Veterans of America/Eastern Paralyzed Veterans Association Neuroscience Research Center, Yale University School of Medicine, New Haven, Connecticut 06510, and ⁴ Rehabilitation Research Center, Veterans Administration Connecticut Healthcare System, West Haven, Connecticut 06516

Voltage-gated Na⁺ currents play critical roles in shaping electrogenesis in neurons. Here, we have identified a TTX-resistant Na⁺ current (TTX-R I_Na) in duodenum myenteric neurons of guinea pig and rat and have sought evidence regarding the molecular identity of the channel producing this current from the expression of Na⁺ channel  subunits and the biophysical and pharmacological properties of TTX-R I_Na. Whole-cell patch-clamp recording from in situ neurons revealed the presence of a voltage-gated Na⁺ current that was highly resistant to TTX (IC₅₀, ~200 µM) and selectively distributed in myenteric sensory neurons but not in interneurons and motor neurons. TTX-R I_Na activated slowly in response to depolarization and exhibited a threshold for activation at -50 mV. V_1/2 values of activation and steady-state inactivation were -32 and -31 mV in the absence of fluoride, respectively, which, as predicted from the window current, generated persistent currents. TTX-R I_Na also had prominent ultraslow inactivation, which turns off 50% of the conductance at rest (-60 mV). Substituting CsF for CsCl in the intracellular solution shifted the voltage-dependent parameters of TTX-R I_Na leftward by ~20 mV. Under these conditions, TTX-R I_Na had voltage-dependent properties similar to those reported previously for NaN/Na_V1.9 in dorsal root ganglion neurons. Consistent with this, reverse transcription-PCR, single-cell profiling, and immunostaining experiments indicated that Na_V1.9 transcripts and subunits, but not Na_V1.8, were expressed in the enteric nervous system and restricted to myenteric sensory neurons. TTX-R I_Na may play an important role in regulating subthreshold electrogenesis and boosting synaptic stimuli, thereby conferring distinct integrative properties to myenteric sensory neurons.

Key words: myenteric sensory neurons; sodium channel; TTX; patch clamp; RT-PCR; immunohistochemistry

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Copyright © 2003 Society for Neuroscience  0270-6474/03/2372715-11$05.00/0

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