Skip to main content
PMC home page
Genetics logoLink to Genetics
. 1999 Dec;153(4):1673–1682. doi: 10.1093/genetics/153.4.1673

A stomatin and a degenerin interact to control anesthetic sensitivity in Caenorhabditis elegans.

S Rajaram 1, T L Spangler 1, M M Sedensky 1, P G Morgan 1
PMCID: PMC1460880  PMID: 10581275

Abstract

The mechanism of action of volatile anesthetics is unknown. In Caenorhabditis elegans, mutations in the gene unc-1 alter anesthetic sensitivity. The protein UNC-1 is a close homologue of the mammalian protein stomatin. Mammalian stomatin is thought to interact with an as-yet-unknown ion channel to control sodium flux. Using both reporter constructs and translational fusion constructs for UNC-1 and green fluorescent protein (GFP), we have shown that UNC-1 is expressed primarily within the nervous system. The expression pattern of UNC-1 is similar to that of UNC-8, a sodium channel homologue. We examined the interaction of multiple alleles of unc-1 and unc-8 with each other and with other genes affecting anesthetic sensitivity. The data indicate that the protein products of these genes interact, and that an UNC-1/UNC-8 complex is a possible anesthetic target. We propose that membrane-associated protein complexes may represent a general target for volatile anesthetics.

Full Text

The Full Text of this article is available as a PDF (146.8 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anton A. H., Berk A. I., Nicholls C. H. The "anesthetic" effect of alcohols and alkanes in Caenorhabditis elegans (C.e.). Res Commun Chem Pathol Pharmacol. 1992 Oct;78(1):69–83. [PubMed] [Google Scholar]
  2. Baker R., Melchior C., Deitrich R. The effect of halothane on mice selectively bred for differential sensitivity to alcohol. Pharmacol Biochem Behav. 1980 May;12(5):691–695. doi: 10.1016/0091-3057(80)90150-1. [DOI] [PubMed] [Google Scholar]
  3. Brenner S. The genetics of Caenorhabditis elegans. Genetics. 1974 May;77(1):71–94. doi: 10.1093/genetics/77.1.71. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chalfie M., Au M. Genetic control of differentiation of the Caenorhabditis elegans touch receptor neurons. Science. 1989 Feb 24;243(4894 Pt 1):1027–1033. doi: 10.1126/science.2646709. [DOI] [PubMed] [Google Scholar]
  5. Chalfie M., Tu Y., Euskirchen G., Ward W. W., Prasher D. C. Green fluorescent protein as a marker for gene expression. Science. 1994 Feb 11;263(5148):802–805. doi: 10.1126/science.8303295. [DOI] [PubMed] [Google Scholar]
  6. Chalfie M., Wolinsky E. The identification and suppression of inherited neurodegeneration in Caenorhabditis elegans. Nature. 1990 May 31;345(6274):410–416. doi: 10.1038/345410a0. [DOI] [PubMed] [Google Scholar]
  7. Crowder C. M., Shebester L. D., Schedl T. Behavioral effects of volatile anesthetics in Caenorhabditis elegans. Anesthesiology. 1996 Oct;85(4):901–912. doi: 10.1097/00000542-199610000-00027. [DOI] [PubMed] [Google Scholar]
  8. Driscoll M., Chalfie M. The mec-4 gene is a member of a family of Caenorhabditis elegans genes that can mutate to induce neuronal degeneration. Nature. 1991 Feb 14;349(6310):588–593. doi: 10.1038/349588a0. [DOI] [PubMed] [Google Scholar]
  9. Eckenhoff R. G. Amino acid resolution of halothane binding sites in serum albumin. J Biol Chem. 1996 Jun 28;271(26):15521–15526. doi: 10.1074/jbc.271.26.15521. [DOI] [PubMed] [Google Scholar]
  10. Eckenhoff R. G. An inhalational anesthetic binding domain in the nicotinic acetylcholine receptor. Proc Natl Acad Sci U S A. 1996 Apr 2;93(7):2807–2810. doi: 10.1073/pnas.93.7.2807. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Franks N. P., Lieb W. R. Molecular and cellular mechanisms of general anaesthesia. Nature. 1994 Feb 17;367(6464):607–614. doi: 10.1038/367607a0. [DOI] [PubMed] [Google Scholar]
  12. Froemming G. R., Dillane D. J., Ohlendieck K. Complex formation of skeletal muscle Ca2+-regulatory membrane proteins by halothane. Eur J Pharmacol. 1999 Jan 15;365(1):91–102. doi: 10.1016/s0014-2999(98)00854-1. [DOI] [PubMed] [Google Scholar]
  13. Gamo S., Ogaki M., Nakashima-Tanaka E. Strain differences in minimum anesthetic concentrations in Drosophila melanogaster. Anesthesiology. 1981 Apr;54(4):289–293. doi: 10.1097/00000542-198104000-00006. [DOI] [PubMed] [Google Scholar]
  14. García-Añoveros J., Derfler B., Neville-Golden J., Hyman B. T., Corey D. P. BNaC1 and BNaC2 constitute a new family of human neuronal sodium channels related to degenerins and epithelial sodium channels. Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1459–1464. doi: 10.1073/pnas.94.4.1459. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gu G., Caldwell G. A., Chalfie M. Genetic interactions affecting touch sensitivity in Caenorhabditis elegans. Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6577–6582. doi: 10.1073/pnas.93.13.6577. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hecht R. M., Norman M. A., Vu T., Jones W. A novel set of uncoordinated mutants in Caenorhabditis elegans uncovered by cold-sensitive mutations. Genome. 1996 Apr;39(2):459–464. doi: 10.1139/g96-058. [DOI] [PubMed] [Google Scholar]
  17. Huang M., Gu G., Ferguson E. L., Chalfie M. A stomatin-like protein necessary for mechanosensation in C. elegans. Nature. 1995 Nov 16;378(6554):292–295. doi: 10.1038/378292a0. [DOI] [PubMed] [Google Scholar]
  18. Kayser E. B., Morgan P. G., Sedensky M. M. GAS-1: a mitochondrial protein controls sensitivity to volatile anesthetics in the nematode Caenorhabditis elegans. Anesthesiology. 1999 Feb;90(2):545–554. doi: 10.1097/00000542-199902000-00031. [DOI] [PubMed] [Google Scholar]
  19. Koblin D. D., Deady J. E. Anaesthetic requirement in mice selectively bred for differences in ethanol sensitivity. Br J Anaesth. 1981 Jan;53(1):5–10. doi: 10.1093/bja/53.1.5. [DOI] [PubMed] [Google Scholar]
  20. Krishnan K. S., Nash H. A. A genetic study of the anesthetic response: mutants of Drosophila melanogaster altered in sensitivity to halothane. Proc Natl Acad Sci U S A. 1990 Nov;87(21):8632–8636. doi: 10.1073/pnas.87.21.8632. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Mayer H., Salzer U., Breuss J., Ziegler S., Marchler-Bauer A., Prohaska R. Isolation, molecular characterization, and tissue-specific expression of a novel putative G protein-coupled receptor. Biochim Biophys Acta. 1998 Feb 11;1395(3):301–308. doi: 10.1016/s0167-4781(97)00178-4. [DOI] [PubMed] [Google Scholar]
  22. McCrae A. F., Gallaher E. J., Winter P. M., Firestone L. L. Volatile anesthetic requirements differ in mice selectively bred for sensitivity or resistance to diazepam: implications for the site of anesthesia. Anesth Analg. 1993 Jun;76(6):1313–1317. doi: 10.1213/00000539-199376060-00022. [DOI] [PubMed] [Google Scholar]
  23. Miller K. W., Firestone L. L., Alifimoff J. K., Streicher P. Nonanesthetic alcohols dissolve in synaptic membranes without perturbing their lipids. Proc Natl Acad Sci U S A. 1989 Feb;86(3):1084–1087. doi: 10.1073/pnas.86.3.1084. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Morgan P. G., Cascorbi H. F. Effect of anesthetics and a convulsant on normal and mutant Caenorhabditis elegans. Anesthesiology. 1985 Jun;62(6):738–744. doi: 10.1097/00000542-198506000-00007. [DOI] [PubMed] [Google Scholar]
  25. Morgan P. G., Sedensky M. M. Mutations conferring new patterns of sensitivity to volatile anesthetics in Caenorhabditis elegans. Anesthesiology. 1994 Oct;81(4):888–898. doi: 10.1097/00000542-199410000-00016. [DOI] [PubMed] [Google Scholar]
  26. Morgan P. G., Sedensky M., Meneely P. M. Multiple sites of action of volatile anesthetics in Caenorhabditis elegans. Proc Natl Acad Sci U S A. 1990 Apr;87(8):2965–2969. doi: 10.1073/pnas.87.8.2965. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Sedensky M. M., Cascorbi H. F., Meinwald J., Radford P., Morgan P. G. Genetic differences affecting the potency of stereoisomers of halothane. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):10054–10058. doi: 10.1073/pnas.91.21.10054. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Seidel G., Prohaska R. Molecular cloning of hSLP-1, a novel human brain-specific member of the band 7/MEC-2 family similar to Caenorhabditis elegans UNC-24. Gene. 1998 Dec 28;225(1-2):23–29. doi: 10.1016/s0378-1119(98)00532-0. [DOI] [PubMed] [Google Scholar]
  29. Shreffler W., Magardino T., Shekdar K., Wolinsky E. The unc-8 and sup-40 genes regulate ion channel function in Caenorhabditis elegans motorneurons. Genetics. 1995 Mar;139(3):1261–1272. doi: 10.1093/genetics/139.3.1261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Snyers L., Umlauf E., Prohaska R. Oligomeric nature of the integral membrane protein stomatin. J Biol Chem. 1998 Jul 3;273(27):17221–17226. doi: 10.1074/jbc.273.27.17221. [DOI] [PubMed] [Google Scholar]
  31. Stewart G. W., Argent A. C., Dash B. C. Stomatin: a putative cation transport regulator in the red cell membrane. Biochim Biophys Acta. 1993 Nov 25;1225(1):15–25. doi: 10.1016/0925-4439(93)90116-i. [DOI] [PubMed] [Google Scholar]
  32. Tavernarakis N., Shreffler W., Wang S., Driscoll M. unc-8, a DEG/ENaC family member, encodes a subunit of a candidate mechanically gated channel that modulates C. elegans locomotion. Neuron. 1997 Jan;18(1):107–119. doi: 10.1016/s0896-6273(01)80050-7. [DOI] [PubMed] [Google Scholar]
  33. Waud D. R. On biological assays involving quantal responses. J Pharmacol Exp Ther. 1972 Dec;183(3):577–607. [PubMed] [Google Scholar]
  34. van Swinderen B., Saifee O., Shebester L., Roberson R., Nonet M. L., Crowder C. M. A neomorphic syntaxin mutation blocks volatile-anesthetic action in Caenorhabditis elegans. Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2479–2484. doi: 10.1073/pnas.96.5.2479. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Genetics are provided here courtesy of Oxford University Press

RESOURCES