title: Nalcn Is a "Leak" Sodium Channel That Regulates Excitability of Brainstem Chemosensory Neurons and Breathing.
abstract: The activity of background potassium and sodium channels determines neuronal excitability, but physiological roles for "leak" Na(+) channels in specific mammalian neurons have not been established. Here, we show that a leak Na(+) channel, Nalcn, is expressed in the CO2/H(+)-sensitive neurons of the mouse retrotrapezoid nucleus (RTN) that regulate breathing. In RTN neurons, Nalcn expression correlated with higher action potential discharge over a more alkalized range of activity; shRNA-mediated depletion of Nalcn hyperpolarized RTN neurons, and reduced leak Na(+) current and firing rate. Nalcn depletion also decreased RTN neuron activation by the neuropeptide, substance P, without affecting pH-sensitive background K(+) currents or activation by a cotransmitter, serotonin. In vivo, RTN-specific knockdown of Nalcn reduced CO2-evoked neuronal activation and breathing; hypoxic hyperventilation was unchanged. Thus, Nalcn regulates RTN neuronal excitability and stimulation by CO2, independent of direct pH sensing, potentially contributing to respiratory effects of Nalcn mutations; transmitter modulation of Nalcn may underlie state-dependent changes in breathing and respiratory chemosensitivity.
  
  
  
  Breathing is an essential, enduring rhythmic motor activity orchestrated by dedicated brainstem circuits that require tonic excitatory drive for their persistent function. A major source of drive is from a group of CO2/H(+)-sensitive neurons in the retrotrapezoid nucleus (RTN), whose ongoing activity is critical for breathing. The ionic mechanisms that support spontaneous activity of RTN neurons are unknown. We show here that Nalcn, a unique channel that generates "leak" sodium currents, regulates excitability and neuromodulation of RTN neurons and CO2-stimulated breathing. Thus, this work defines a specific function for this enigmatic channel in an important physiological context.
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908.
authors.forename: Yingtang
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908.
authors.forename: Chikara
authors.initials: C
authors.lastname: Abe
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908.
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Holloway
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908.
authors.forename: Shaofang
authors.identifier: 0000-0001-8088-0244
authors.initials: S
authors.lastname: Shu
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908.
authors.forename: Natasha N
authors.initials: NN
authors.lastname: Kumar
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908.
authors.forename: Janelle L
authors.identifier: 0000-0001-8677-8312
authors.initials: JL
authors.lastname: Weaver
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908.
authors.forename: Josh
authors.initials: J
authors.lastname: Sen
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908.
authors.forename: Edward
authors.initials: E
authors.lastname: Perez-Reyes
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908.
authors.forename: Ruth L
authors.identifier: 0000-0001-7278-8923
authors.initials: RL
authors.lastname: Stornetta
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908.
authors.forename: Patrice G
authors.identifier: 0000-0003-1739-2306
authors.initials: PG
authors.lastname: Guyenet
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908 bayliss@virginia.edu.
authors.forename: Douglas A
authors.identifier: 0000-0002-5630-2572
authors.initials: DA
authors.lastname: Bayliss
mesh_terms: D000818:Animals; D002245:Carbon Dioxide / Q000378:metabolism; D002478:Cells, Cultured; D063226:Central Pattern Generators / Q000502:physiology*; D002628:Chemoreceptor Cells / Q000502:physiology*; D005260:Female; D015640:Ion Channel Gating / Q000502:physiology; D007473:Ion Channels / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D015656:Respiratory Mechanics / Q000502:physiology*; D012964:Sodium / Q000378:metabolism*; D065832:Superior Olivary Complex / Q000502:physiology*
chemical_list: D007473:Ion Channels; D008565:Membrane Proteins; C519922:NALCN protein, mouse; D009419:Nerve Tissue Proteins; D002245:Carbon Dioxide; D012964:Sodium
keywords: Phox2b; respiratory chemoreceptors; retrotrapezoid nucleus; substance P; ventilation