A microarray analysis of potential genes underlying the neurosensitivity of mice to propofol.
Establishing the mechanism of action of general anesthetics at the molecular level is difficult because of the multiple targets with which these drugs are associated. Inbred short sleep (ISS) and long sleep (ILS) mice are differentially sensitive in response to ethanol and other sedative hypnotics and contain a single quantitative trait locus (Lorp1) that accounts for the genetic variance of loss-of-righting reflex in response to propofol (LORP). In this study, we used high-density oligonucleotide microarrays to identify global gene expression and candidate genes differentially expressed within the Lorp1 region that may give insight into the molecular mechanism underlying LORP. Microarray analysis was performed using Affymetrix MG-U74Av2 Genechips and a selection of differentially expressed genes was confirmed by semiquantitative reverse transcription-polymerase chain reaction. Global expression in the brains of ILS and ISS mice revealed 3423 genes that were significantly expressed, of which 139 (4%) were differentially expressed. Analysis of genes located within the Lorp1 region showed that 26 genes were significantly expressed and that just 2 genes (7%) were differentially expressed. These genes encoded for the proteins AWP1 (associated with protein kinase 1) and "BTB (POZ) domain containing 1," whose functions are largely uncharacterized. Genes differentially expressed outside Lorp1 included seven genes with previously characterized neuronal functions and thus stand out as additional candidate genes that may be involved in mediating the neurosensitivity differences between ISS and ILS.
Lowes
Damon A
DA
*Academic Unit of Anaesthesia and Intensive Care, University of Aberdeen, Scotland, United Kingdom; and †Institute for Behavioral Genetics, University of Colorado at Boulder, Boulder, Colorado.
Galley
Helen F
HF
Lowe
Peter R
PR
Rikke
Brad A
BA
Johnson
Thomas E
TE
Webster
Nigel R
NR
D018686:Anesthetics, Intravenous / Q000633:toxicity*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects / Q000235:genetics; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D015870:Gene Expression / Q000502:physiology; D051379:Mice; D008815:Mice, Inbred Strains; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D015742:Propofol / Q000633:toxicity*; D018075:RNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012890:Sleep / Q000235:genetics
D018686:Anesthetics, Intravenous; D018076:DNA, Complementary; D018075:RNA, Complementary; D015742:Propofol