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Malfunction of respiratory-related neuronal activity in Na+, K+-ATPase alpha2 subunit-deficient mice is attributable to abnormal Cl- homeostasis in brainstem neurons.


Na+, K+-ATPase 2 subunit gene (Atp1a2) knock-out homozygous mice (Atp1a2-/-) died immediately after birth resulting from lack of breathing. The respiratory-related neuron activity in Atp1a2-/- was investigated using a brainstem-spinal cord en bloc preparation. The respiratory motoneuron activity recorded from the fourth cervical ventral root (C4) was defective in Atp1a2-/- fetuses of embryonic day 18.5. The C4 response to electrical stimulation of the ventrolateral medulla (VLM) recovered more slowly in Atp1a2-/- than in wild type during superfusion with Krebs' solution, consistent with the high extracellular GABA in brain of Atp1a2-/-. Lack of inhibitory neural activities in VLM of Atp1a2-/- was observed by optical recordings. High intracellular Cl- concentrations in neurons of the VLM of Atp1a2-/- were detected in gramicidin-perforated patch-clamp recordings. The alpha2 subunit and a neuron-specific K-Cl cotransporter KCC2 were coimmunoprecipitated in a purified synaptic membrane fraction of wild-type fetuses. Based on these results, we propose a model for functional coupling between the Na+, K+-ATPase alpha2 subunit and KCC2, which excludes Cl- from the cytosol in respiratory center neurons.

Pubmed ID: 15564586


  • Ikeda K
  • Onimaru H
  • Yamada J
  • Inoue K
  • Ueno S
  • Onaka T
  • Toyoda H
  • Arata A
  • Ishikawa TO
  • Taketo MM
  • Fukuda A
  • Kawakami K


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

Publication Data

November 24, 2004

Associated Grants


Mesh Terms

  • Amino Acid Sequence
  • Animals
  • Apnea
  • Chlorides
  • Electric Stimulation
  • Facial Nerve
  • Fetus
  • Homeostasis
  • Isoenzymes
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Neural Inhibition
  • Neurons
  • Patch-Clamp Techniques
  • Potassium
  • Respiratory Center
  • Sodium-Potassium-Exchanging ATPase
  • Spinal Nerve Roots
  • Symporters
  • gamma-Aminobutyric Acid