Single KATP channel opening in response to stimulation of AMPA/kainate receptors is mediated by Na+ accumulation and submembrane ATP and ADP changes

Authors

  • R. Mollajew,

    1. DFG-Center of Molecular Physiology of the Brain, Institute of Neuro- and Sensory Physiology, Georg-August-University, Göttingen 37073, Germany
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  • J. Toloe,

    1. DFG-Center of Molecular Physiology of the Brain, Institute of Neuro- and Sensory Physiology, Georg-August-University, Göttingen 37073, Germany
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  • S. L. Mironov

    1. DFG-Center of Molecular Physiology of the Brain, Institute of Neuro- and Sensory Physiology, Georg-August-University, Göttingen 37073, Germany
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S. L. Mironov: DFG-Center of Molecular Physiology of the Brain, Institute of Neuro- and Sensory Physiology, Georg-August-University, Göttingen 37073, Germany. Email: smirono@gwdg.de

Key points

  • • KATP channels can suppress overexcitation of CNS neurons after activation of glutamatergic receptors (GluRs), and we examined this functional interaction in the brainstem and hippocampal neurons.
  • • GluR stimulation increased the activity of single KATP channels that was not mediated by intracellular calcium, reactive oxygen species and osmotic stress, and was abolished after inhibition of sodium influx.
  • • ATP and sodium imaging indicated that functional cross-talk between GluRs and KATP channels is mediated by Na+-K+-ATPase.
  • • GluR contributed to KATP channel opening during hypoxia in functionally intact brainstem slices and seizure-like activity in the hippocampal slices.
  • • We propose that neuronal activity depletes submembrane ATP, and increases ADP levels and promotes KATP channel opening that dampen uncontrolled excitation by glutamate.

Abstract  Excessive stimulation of glutamatergic receptors (GluRs) can overexcite neurons. This can be dampened by KATP channels linking metabolic and neuronal activities, but the cross-talk has not yet been examined on the single channel level. In the brainstem and hippocampal neurons, GluR agonists augmented the open state probability (Popen) of KATP channels with relative efficacy: kainate ≈ AMPA > NMDA > t-ACPD. Inhibition of calcium influx and chelation of intracellular calcium did not modify the effects. Kainate did not augment production of reactive oxygen species measured with roGFP1. H2O2 slightly increased Popen, but GluR effects were not modified. GluR actions were abolished in Na+-free solutions and after blockade of Na+-K+-ATPase. KATP channels in open-cell patch-clamp measurements were inhibited by ATP, stimulated by ADP, and kainate was effective only in the presence of ATP. GluR stimulation enhanced ATP consumption that decreased submembrane ATP levels, whereas metabolic poisoning diminished bulk ATP. Modelling showed strong ATP depletion and ADP accumulation near the membrane, and both effects contributed to Popen increases after GluR stimulation. Kainate and hypoxia activated KATP channels in the functional brainstem slices. Inhibition of aerobic ATP production and GluR stimulation were about equally effective in KATP channel opening during hypoxia. Induction of seizure-like activity in hippocampal slices with Mg2+-free solutions was accompanied by ATP decrease and KATP channel opening. We propose that KATP channels and GluRs are functionally coupled that can regulate long-lasting changes of neuronal activity in the CNS neurons.

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