In addition to inducing the physiologic state called
anesthesia, volatile anesthetics affect all cells tested. The cellular
basis of any effects of these agents has not been defined. In yeast,
cell division is inhibited. Genetic analysis of yeast mutants that grow
in a normally inhibitory atmosphere of volatile anesthetic identified
seven different genes, ZZZ1-ZZZ7 , that confer resistance when
mutated. Analysis of double mutant strains shows that mutations in all
seven genes interact epistatically, suggesting that the gene products
may be components of a single pathway. The ZZZ1 , ZZZ2 , and
ZZZ4 genes have been cloned and analyzed. ZZZ2 is
UBC4 , which encodes an enzyme required for conjugation of
ubiquitin to certain substrates. The product of ZZZ1 , also called
BUL1 , binds directly to ubiquitin ligase. ZZZ4 has been
identified as DOA1/UFD3 . Doa1/ufd3/zzz4 mutants have
altered protein degradation and low intracellular levels of ubiquitin.
Deletion of ZZZ1 , ZZZ2 , or ZZZ4 renders cells
anesthetic resistant, indicating that absence of the gene product alters
cellular sensitivity. Thus ubiquitination, a posttranslational
modification that can alter turnover or function of a protein, affects
cellular response to anesthetics. Our findings are consistent with
models in which anesthetic exposure directly stimulates the
ubiquitination path or with models in which ubiquitination indirectly
affects cellular response by regulating the activity or level of an
anesthetic target.
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