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Molecular and Cellular Biology, December 1999, p. 8254-8262, Vol. 19, No. 12
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Ubiquitin Metabolism Affects Cellular Response to Volatile Anesthetics in Yeast

Darren Wolfe,dagger Thomas Reiner, Jessica L. Keeley, Mark Pizzini,Dagger and Ralph L. Keil*

Department of Biochemistry and Molecular Biology, The Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, Pennsylvania, 17033-2390

Received 22 April 1999/Returned for modification 10 June 1999/Accepted 1 September 1999

To investigate the mechanism of action of volatile anesthetics, we are studying mutants of the yeast Saccharomyces cerevisiae that have altered sensitivity to isoflurane, a widely used clinical anesthetic. Several lines of evidence from these studies implicate a role for ubiquitin metabolism in cellular response to volatile anesthetics: (i) mutations in the ZZZ1 gene render cells resistant to isoflurane, and the ZZZ1 gene is identical to BUL1 (binds ubiquitin ligase), which appears to be involved in the ubiquitination pathway; (ii) ZZZ4, which we previously found is involved in anesthetic response, is identical to the DOA1/UFD3 gene, which was identified based on altered degradation of ubiquitinated proteins; (iii) analysis of zzz1Delta zzz4Delta double mutants suggests that these genes encode products involved in the same pathway for anesthetic response since the double mutant is no more resistant to anesthetic than either of the single mutant parents; (iv) ubiquitin ligase (MDP1/RSP5) mutants are altered in their response to isoflurane; and (v) mutants with decreased proteasome activity are resistant to isoflurane. The ZZZ1 and MDP1/RSP5 gene products appear to play important roles in determining effective anesthetic dose in yeast since increased levels of either gene increases isoflurane sensitivity whereas decreased activity decreases sensitivity. Like zzz4 strains, zzz1 mutants are resistant to all five volatile anesthetics tested, suggesting there are similarities in the mechanisms of action of a variety of volatile anesthetics in yeast and that ubiquitin metabolism affects response to all the agents examined.

* Corresponding author. Mailing address: Department of Biochemistry and Molecular Biology, H171, The Milton S. Hershey Medical Center, 500 University Dr., The Pennsylvania State University, Hershey, PA 17033-2390. Phone: (717) 531-8595. Fax: (717) 531-7072. E-mail: rkeil{at}psu.edu.

dagger Present address: Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261.

Dagger Present address: Department of Anesthesiology, Fox Chase Cancer Center, Philadelphia, PA 19104.

Molecular and Cellular Biology, December 1999, p. 8254-8262, Vol. 19, No. 12
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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