Reversible inhibition of protein synthesis in lung by halothane

Rannels, D. E.; Christopherson, Richard I.; Watkins, C. A.

doi:10.1042/bj2100379

Cited by 18 publications

(14 citation statements)

References 40 publications

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“…Furthermore, the anaesthetic and general stress associated with these types of procedures may have a depressive effect on the rates of protein synthesis in teleosts. This has previously been observed in mammals (Rannels et al 1983;Sakamoto et al 1983;Rennie and MacLennan 1985).…”

Section: Introductionsupporting

confidence: 50%

Protein synthesis in tissues of fed and starved carp, acclimated to different temperatures

Watt

Marshall

Heap

et al. 1988

Fish Physiol Biochem

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The temperature dependence of the rates of protein synthesis in the red and white skeletal muscle of the carp (Cyprinus carpio) was measured using a method which involved a single injection of tritiated phenylalanine. Plasma and muscle-free phenylalanine quickly reached a plateau level at all temperatures. During the plateau phase the incorporation of label into protein was liner. Muscle from fish previously acclimated to either a low temperature (8°C) or a high temperature (28°C), showed marked differences in the rates of protein synthesis. The results show that cold acclimation is associated with significantly higher rates of protein synthesis (p<0.001) in both red and white muscle. Arrhenius activation energies, derived from the rates of protein synthesis at the different experimental temperatures, were similar for both red and white muscle in fish acclimated to warm or cold temperatures. Measurements for both acclimated groups over the temperature range 8-34°C showed that the activation energy for the process of protein synthesis was 86.7 kJ/mol and 78.7 kJ/mol for the red and white muscle respectively.

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Section: Introductionsupporting

confidence: 50%

Protein synthesis in tissues of fed and starved carp, acclimated to different temperatures

Watt

Marshall

Heap

et al. 1988

Fish Physiol Biochem

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“…One volume of detergent mix (10% Triton X-100 and 10% sodium deoxycholate) was added to 9 vol of supernatant. A 500-l aliquot of this mixture was layered onto a 20 -48% SDG formed by alternately adding and freezing (in liquid nitrogen) 1.45-ml aliquots of 20,24,28,32,36,40,44, and 48% sucrose in SDG buffer. Before use, gradients were thawed overnight at 4°C.…”

Section: Methodsmentioning

confidence: 99%

“…This has been reported in a number of different systems, including intact animals (23)(24)(25), perfused organs (10,40,41), tissue slices in culture (15)(16)(17)(18), and cells in culture (3,6,8,21,35). Studies regarding effects of volatile anesthetics on protein synthesis in perfused rat liver, the system employed in the work reported here, demonstrate that halothane exposure produces a rapid and dose-dependent inhibition of translation initiation affecting synthesis of both secreted and retained proteins (10,12).…”

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confidence: 99%

Inhibition of mammalian translation initiation by volatile anesthetics

Palmer¹,

Rannels²,

Kimball³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

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Volatile anesthetics are essential for modern medical practice, but sites and mechanisms of action for any of their numerous cellular effects remain largely unknown. Previous studies with yeast showed that volatile anesthetics induce nutrient-dependent inhibition of growth through mechanisms involving inhibition of mRNA translation. Studies herein show that the volatile anesthetic halothane inhibits protein synthesis in perfused rat liver at doses ranging from 2 to 6%. A marked disaggregation of polysomes occurs, indicating that inhibition of translation initiation plays a key role. Dose-and time-dependent alterations that decrease the function of a variety of translation initiation processes are observed. At 6% halothane, a rapid and persistent increase in phosphorylation of the ␣-subunit of eukaryotic translation initiation factor (eIF)2 occurs. This is accompanied by inhibition of activity of the guanine nucleotide exchange factor eIF2B that is responsible for GDP-GTP exchange on eIF2. At lower doses, neither eIF2␣ phosphorylation nor eIF2B activity is altered. After extended exposure to 6% halothane, alterations in two separate responses regulated by the target of rapamycin pathway occur: 1) redistribution of eIF4E from its translation-stimulatory association with eIF4G to its translation-inactive complex with eIF4E-binding protein-1; and 2) decreased phosphorylation of ribosomal protein S6 (rpS6) with a corresponding decrease in active forms of a kinase that phosphorylates rpS6 (p70 S6K1 ). Changes in the association of eIF4E and eIF4G are observed only after extended exposure to low anesthetic doses. Thus dose-and time-dependent alterations in multiple processes permit liver cells to adapt translation to variable degrees and duration of stress imposed by anesthetic exposure. halothane; eukaryotic translation initiation factor 2␣ phosphorylation; mammalian target of rapamycin pathway ALTHOUGH VOLATILE ANESTHETICS revolutionized medical practice when introduced in 1846, the mechanisms of action responsible for the physiological effects of these drugs remain essentially unknown. In addition to affecting cells of the central nervous system, these drugs affect all cells, tissues, and organisms examined (4,26,36). Molecular genetic studies with the small, relatively simple eukaryote Saccharomyces cerevisiae (yeast) provide an opportunity for gaining insight regarding physiologically relevant effects of these drugs (28) and generating hypotheses that are testable in more complex eukaryotes. Extensive similarities exist between the activity of these drugs in mammals and simpler eukaryotes, such as yeast, suggesting conservation of cellular mechanisms responsible for the responses (28,34,45). These similarities include rapid and reversible induction of responses, a sharp dose-response curve, correlation between the lipophilicity of various anesthetics and their potency for inducing responses (termed the Meyer-Overton relationship), additivity of doses of different anesthetics in producing effects, and lack of effec...

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“…Numerous studies in mammalian systems show protein synthesis decreases during anesthetic exposure (e.g., Hammer and Rannels, 1981;Wartell et al, 1981;Rannels et al, 1982Rannels et al, , 1983Flaim et al, 1983). Inhibition is rapid, dose dependent, and reversible and does not result in extensive cell damage or death.…”

Section: Anesthetic-induced Inhibition Of Protein Synthesis In Mammalmentioning

confidence: 99%

Inhibition of Translation Initiation by Volatile Anesthetics Involves Nutrient-sensitive GCN-independent and -dependent Processes in Yeast

Palmer

Shoemaker

Baptiste

et al. 2005

MBoC

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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 zzz3-1 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 ␣ subunit of eukaryotic initiation factor 2 (eIF2␣). Hyperphosphorylation of eIF2␣ inhibits translation initiation during amino acid starvation. Isoflurane rapidly (in <15 min) inhibits yeast cell division and amino acid uptake. Unexpectedly, phosphorylation of eIF2␣ decreased dramatically upon initial exposure although hyperphosphorylation occurred later. Translation initiation was inhibited by isoflurane even when eIF2␣ phosphorylation decreased and this inhibition was GCN-independent. Maintenance of inhibition required GCN-dependent hyperphosphorylation of eIF2␣. 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 eIF2␣ phosphorylation. Surprisingly, as shown here, the transcription activator Gcn4p does not affect anesthetic response.

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Reversible inhibition of protein synthesis in lung by halothane

Cited by 18 publications

References 40 publications

Protein synthesis in tissues of fed and starved carp, acclimated to different temperatures

Protein synthesis in tissues of fed and starved carp, acclimated to different temperatures

Inhibition of mammalian translation initiation by volatile anesthetics

Inhibition of Translation Initiation by Volatile Anesthetics Involves Nutrient-sensitive GCN-independent and -dependent Processes in Yeast

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