Effect of PSD-95/SAP90 and/or PSD-93/chapsyn-110 deficiency on the minimum alveolar anesthetic concentration of halothane in mice

Anesthesiology. 2010 Jun;112(6):1444-51. doi: 10.1097/ALN.0b013e3181dcd3dc.

Abstract

Background: The authors have previously shown that the clinically relevant concentrations of inhalational anesthetics dose-dependently inhibit the postsynaptic density protein (PSD)-95, Dlg, and ZO-1 domain-mediated protein interactions between N-methyl-d-aspartate receptors and PSD-95/synaptic-associated protein (SAP) 90 or PSD-93/Chapsyn-110 and that the knockdown of spinal PSD-95/SAP90 significantly reduces the minimum alveolar concentration (MAC) for isoflurane in rats.

Methods: The authors designed antisense oligodeoxynucleotides based on the mouse PSD-95/SAP90 and PSD-93/Chapsyn-110 messenger RNAs that correspond to their PSD-95, Dlg, and ZO-1 domain nucleotides and can specifically knock down the respective proteins. The authors intrathecally injected antisense oligodeoxynucleotides into wild-type and PSD-93/Chapsyn-110 knockout mice to investigate the effect of PSD-95/SAP90 and/or PSD-93/Chapsyn-110 deficiency on halothane anesthesia.

Results: Both PSD-95/SAP90 and PSD-93/Chapsyn-110 antisense oligodeoxynucleotides caused a dose-dependent and significant reduction in the MAC of halothane in wild-type mice. The intrathecal injection of PSD-95/SAP90 antisense oligodeoxynucleotide at different doses (25 and 50 microg) reduced halothane MAC by 40 and 55%, respectively, and intrathecal injection of PSD-93/Chapsyn-110 antisense oligodeoxynucleotide at different doses (12 and 24 microg) reduced halothane MAC by 25 and 53%, respectively. The PSD-95/SAP90 antisense oligodeoxynucleotide showed similar effect on halothane MAC in wild-type and PSD-93/Chapsyn-110 knockout mice, suggesting that the combination of PSD-95/SAP90 knockdown with PSD-93/Chapsyn-110 deletion did not have an additive effect on halothane anesthesia.

Conclusions: The current results indicate that PSD-95/SAP90 and PSD-93/Chapsyn-110 are involved in the molecular mechanisms of halothane anesthesia and that the functional role of PSD-95/SAP90 in halothane anesthesia is not enhanced after PSD-93/Chapsyn-110 deletion.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Anesthetics, Inhalation / administration & dosage
  • Anesthetics, Inhalation / metabolism*
  • Animals
  • Disks Large Homolog 4 Protein
  • Guanylate Kinases
  • Halothane / administration & dosage
  • Halothane / metabolism*
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
  • Intracellular Signaling Peptides and Proteins / deficiency*
  • Intracellular Signaling Peptides and Proteins / genetics
  • Male
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / deficiency*
  • Membrane Proteins / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Motor Activity / genetics
  • Oligodeoxyribonucleotides, Antisense / administration & dosage
  • Pulmonary Alveoli / drug effects
  • Pulmonary Alveoli / metabolism*

Substances

  • Anesthetics, Inhalation
  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Oligodeoxyribonucleotides, Antisense
  • Dlg2 protein, mouse
  • Guanylate Kinases
  • Halothane