Inhibition of translation initiation by volatile anesthetics involves nutrient-sensitive GCN-independent and -dependent processes in yeast

Laura K. Palmer, Jessica L. Shoemaker, Beverly A. Baptiste, Darren Wolfe, Ralph L. Keil

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Volatile anesthetics including isoflurane affect all cells examined, but their mechanisms of action remain unknown. To investigate the cellular basis of anesthetic action, we are studying Saccharomyces cerevisiae mutants altered in their response to anesthetics. The zzz3-l mutation renders yeast isoflurane resistant and is an allele of GCN3. Gcn3p functions in the evolutionarily conserved general amino acid control (GCN) pathway that regulates protein synthesis and gene expression in response to nutrient availability through phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α). Hyperphosphorylation of eIF2α inhibits translation initiation during amino acid starvation. Isoflurane rapidly (in <15 min) inhibits yeast cell division and amino acid uptake. Unexpectedly, phosphorylation of eIF2α decreased dramatically upon initial exposure although hyperphosphorylation occurred later. Translation initiation was inhibited by isoflurane even when eIF2α phosphorylation decreased and this inhibition was GCN-independent. Maintenance of inhibition required GCN-dependent hyperphosphorylation of eIF2α. Thus, two nutrient-sensitive stages displaying unique features promote isoflurane-induced inhibition of translation initiation. The rapid phase is GCN-independent and apparently has not been recognized previously. The maintenance phase is GCN-dependent and requires inhibition of general translation imparted by enhanced eIF2α phosphorylation. Surprisingly, as shown here, the transcription activator Gcn4p does not affect anesthetic response.

Original languageEnglish (US)
Pages (from-to)3727-3739
Number of pages13
JournalMolecular biology of the cell
Volume16
Issue number8
DOIs
StatePublished - Aug 1 2005

Fingerprint

Eukaryotic Initiation Factor-2
Anesthetics
Isoflurane
Yeasts
Amino Acids
Food
Phosphorylation
Maintenance
Starvation
Cell Division
Saccharomyces cerevisiae
Alleles
Gene Expression
Mutation

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

@article{d632c03394d74401be30c1dddd694387,
title = "Inhibition of translation initiation by volatile anesthetics involves nutrient-sensitive GCN-independent and -dependent processes in yeast",
abstract = "Volatile anesthetics including isoflurane affect all cells examined, but their mechanisms of action remain unknown. To investigate the cellular basis of anesthetic action, we are studying Saccharomyces cerevisiae mutants altered in their response to anesthetics. The zzz3-l mutation renders yeast isoflurane resistant and is an allele of GCN3. Gcn3p functions in the evolutionarily conserved general amino acid control (GCN) pathway that regulates protein synthesis and gene expression in response to nutrient availability through phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α). Hyperphosphorylation of eIF2α inhibits translation initiation during amino acid starvation. Isoflurane rapidly (in <15 min) inhibits yeast cell division and amino acid uptake. Unexpectedly, phosphorylation of eIF2α decreased dramatically upon initial exposure although hyperphosphorylation occurred later. Translation initiation was inhibited by isoflurane even when eIF2α phosphorylation decreased and this inhibition was GCN-independent. Maintenance of inhibition required GCN-dependent hyperphosphorylation of eIF2α. Thus, two nutrient-sensitive stages displaying unique features promote isoflurane-induced inhibition of translation initiation. The rapid phase is GCN-independent and apparently has not been recognized previously. The maintenance phase is GCN-dependent and requires inhibition of general translation imparted by enhanced eIF2α phosphorylation. Surprisingly, as shown here, the transcription activator Gcn4p does not affect anesthetic response.",
author = "Palmer, {Laura K.} and Shoemaker, {Jessica L.} and Baptiste, {Beverly A.} and Darren Wolfe and Keil, {Ralph L.}",
year = "2005",
month = "8",
day = "1",
doi = "10.1091/mbc.E05-02-0127",
language = "English (US)",
volume = "16",
pages = "3727--3739",
journal = "Molecular Biology of the Cell",
issn = "1059-1524",
publisher = "American Society for Cell Biology",
number = "8",

}

Inhibition of translation initiation by volatile anesthetics involves nutrient-sensitive GCN-independent and -dependent processes in yeast. / Palmer, Laura K.; Shoemaker, Jessica L.; Baptiste, Beverly A.; Wolfe, Darren; Keil, Ralph L.

In: Molecular biology of the cell, Vol. 16, No. 8, 01.08.2005, p. 3727-3739.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Inhibition of translation initiation by volatile anesthetics involves nutrient-sensitive GCN-independent and -dependent processes in yeast

AU - Palmer, Laura K.

AU - Shoemaker, Jessica L.

AU - Baptiste, Beverly A.

AU - Wolfe, Darren

AU - Keil, Ralph L.

PY - 2005/8/1

Y1 - 2005/8/1

N2 - Volatile anesthetics including isoflurane affect all cells examined, but their mechanisms of action remain unknown. To investigate the cellular basis of anesthetic action, we are studying Saccharomyces cerevisiae mutants altered in their response to anesthetics. The zzz3-l mutation renders yeast isoflurane resistant and is an allele of GCN3. Gcn3p functions in the evolutionarily conserved general amino acid control (GCN) pathway that regulates protein synthesis and gene expression in response to nutrient availability through phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α). Hyperphosphorylation of eIF2α inhibits translation initiation during amino acid starvation. Isoflurane rapidly (in <15 min) inhibits yeast cell division and amino acid uptake. Unexpectedly, phosphorylation of eIF2α decreased dramatically upon initial exposure although hyperphosphorylation occurred later. Translation initiation was inhibited by isoflurane even when eIF2α phosphorylation decreased and this inhibition was GCN-independent. Maintenance of inhibition required GCN-dependent hyperphosphorylation of eIF2α. Thus, two nutrient-sensitive stages displaying unique features promote isoflurane-induced inhibition of translation initiation. The rapid phase is GCN-independent and apparently has not been recognized previously. The maintenance phase is GCN-dependent and requires inhibition of general translation imparted by enhanced eIF2α phosphorylation. Surprisingly, as shown here, the transcription activator Gcn4p does not affect anesthetic response.

AB - Volatile anesthetics including isoflurane affect all cells examined, but their mechanisms of action remain unknown. To investigate the cellular basis of anesthetic action, we are studying Saccharomyces cerevisiae mutants altered in their response to anesthetics. The zzz3-l mutation renders yeast isoflurane resistant and is an allele of GCN3. Gcn3p functions in the evolutionarily conserved general amino acid control (GCN) pathway that regulates protein synthesis and gene expression in response to nutrient availability through phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α). Hyperphosphorylation of eIF2α inhibits translation initiation during amino acid starvation. Isoflurane rapidly (in <15 min) inhibits yeast cell division and amino acid uptake. Unexpectedly, phosphorylation of eIF2α decreased dramatically upon initial exposure although hyperphosphorylation occurred later. Translation initiation was inhibited by isoflurane even when eIF2α phosphorylation decreased and this inhibition was GCN-independent. Maintenance of inhibition required GCN-dependent hyperphosphorylation of eIF2α. Thus, two nutrient-sensitive stages displaying unique features promote isoflurane-induced inhibition of translation initiation. The rapid phase is GCN-independent and apparently has not been recognized previously. The maintenance phase is GCN-dependent and requires inhibition of general translation imparted by enhanced eIF2α phosphorylation. Surprisingly, as shown here, the transcription activator Gcn4p does not affect anesthetic response.

UR - http://www.scopus.com/inward/record.url?scp=23044493412&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=23044493412&partnerID=8YFLogxK

U2 - 10.1091/mbc.E05-02-0127

DO - 10.1091/mbc.E05-02-0127

M3 - Article

C2 - 15930127

AN - SCOPUS:23044493412

VL - 16

SP - 3727

EP - 3739

JO - Molecular Biology of the Cell

JF - Molecular Biology of the Cell

SN - 1059-1524

IS - 8

ER -