Dataset Information

Nalcn Is a "Leak" Sodium Channel That Regulates Excitability of Brainstem Chemosensory Neurons and Breathing.

ABSTRACT: UNLABELLED: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. SIGNIFICANCE STATEMENT: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.

SUBMITTER: Shi Y

PROVIDER: S-EPMC4971364 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Nalcn Is a "Leak" Sodium Channel That Regulates Excitability of Brainstem Chemosensory Neurons and Breathing.

Shi Yingtang Y Abe Chikara C Holloway Benjamin B BB Shu Shaofang S Kumar Natasha N NN Weaver Janelle L JL Sen Josh J Perez-Reyes Edward E Stornetta Ruth L RL Guyenet Patrice G PG Bayliss Douglas A DA

The Journal of neuroscience : the official journal of the Society for Neuroscience 20160801 31

<h4>Unlabelled</h4>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 activit ...[more]

PMID: 27488637

Similar Datasets

Project description:Background/aimsUterine contractility is controlled by electrical signals generated by myometrial smooth muscle cells. Because aberrant electrical signaling may cause inefficient uterine contractions and poor reproductive outcomes, there is great interest in defining the ion channels that regulate uterine excitability. In human myometrium, the Na+ leak channel, non-selective (NALCN) contributes to a gadolinium-sensitive, Na+-dependent leak current. The aim of this study was to determine the role of NALCN in regulating uterine excitability and examine its involvement in parturition.MethodsWildtype C57BL/6J mice underwent timed-mating and NALCN uterine expression was measured at several time points across pregnancy including pregnancy days 7, 10, 14, 18 and 19. Sharp electrode current clamp was used to measure uterine excitability at these same time points. To determine NALCN's contribution to myometrial excitability and pregnancy outcomes, we created smooth-muscle-specific NALCN knockout mice by crossing NALCNfx/fx mice with myosin heavy chain Cre (MHCCreeGFP) mice. Parturition outcomes were assessed by observation via surveillance video recording cre control, flox control, smNALCN+/-, and smNALCN-/- mice. Myometrial excitability was compared between pregnancy day 19 flox controls and smNALCN-/- mice.ResultsWe found that in the mouse uterus, NALCN protein levels were high early in pregnancy, decreased in mid and late pregnancy, and then increased in labor and postpartum. Sharp electrode current clamp recordings of mouse longitudinal myometrial samples from pregnancy days 7, 10, 14, 18, and 19 revealed day-dependent increases in burst duration and interval and decreases in spike density. NALCN smooth muscle knockout mice had reduced myometrial excitability exemplified by shortened action potential bursts, and an increased rate of abnormal labor, including prolonged and dysfunctional labor.ConclusionsTogether, our findings demonstrate that the Na+ conducting channel NALCN contributes to the myometrial action potential waveform and is important for successful labor outcomes.

Project description:BackgroundVolatile anesthetics moderately depress respiratory function at clinically relevant concentrations. Phox2b-expressing chemosensitive neurons in the retrotrapezoid nucleus, a respiratory control center, are activated by isoflurane, but the underlying mechanisms remain unclear. The hypothesis of this study was that the sodium leak channel contributes to the volatile anesthetics-induced modulation of retrotrapezoid nucleus neurons and to respiratory output.MethodsThe contribution of sodium leak channels to isoflurane-, sevoflurane-, and propofol-evoked activity of Phox2b-expressing retrotrapezoid nucleus neurons and respiratory output were evaluated in wild-type and genetically modified mice lacking sodium leak channels (both sexes). Patch-clamp recordings were performed in acute brain slices. Whole-body plethysmography was used to measure the respiratory activity.ResultsIsoflurane at 0.42 to 0.50 mM (~1.5 minimum alveolar concentration) increased the sodium leak channel-mediated holding currents and conductance from -75.0 ± 12.9 to -130.1 ± 34.9 pA (mean ± SD, P = 0.002, n = 6) and 1.8 ± 0.5 to 3.6 ± 1.0 nS (P = 0.001, n = 6), respectively. At these concentrations, isoflurane increased activity of Phox2b-expressing retrotrapezoid nucleus neurons from 1.1 ± 0.2 to 2.8 ± 0.2 Hz (P < 0.001, n = 5), which was eliminated by bath application of gadolinium or genetic silencing of sodium leak channel. Genetic silencing of sodium leak channel in the retrotrapezoid nucleus resulted in a diminished ventilatory response to carbon dioxide in mice under control conditions and during isoflurane anesthesia. Sevoflurane produced an effect comparable to that of isoflurane, whereas propofol did not activate sodium leak channel-mediated holding conductance.ConclusionsIsoflurane and sevoflurane increase neuronal excitability of chemosensitive retrotrapezoid nucleus neurons partly by enhancing sodium leak channel conductance. Sodium leak channel expression in the retrotrapezoid nucleus is required for the ventilatory response to carbon dioxide during anesthesia by isoflurane and sevoflurane, thus identifying sodium leak channel as a requisite determinant of respiratory output during anesthesia of volatile anesthetics.Editor’s perspective

Dataset Information

Nalcn Is a "Leak" Sodium Channel That Regulates Excitability of Brainstem Chemosensory Neurons and Breathing.

Publications

Nalcn Is a "Leak" Sodium Channel That Regulates Excitability of Brainstem Chemosensory Neurons and Breathing.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets