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Volume 17, Number 15, Issue of August 1, 1997 pp. 5843-5857
Copyright ©1997 Society for Neuroscience

Caenorhabditis elegans Levamisole Resistance Genes lev-1, unc-29, and unc-38 Encode Functional Nicotinic Acetylcholine Receptor Subunits

Received March 31, 1997; accepted May 14, 1997.

John T. Fleming1, 6, Michael D. Squire2, 3, Thomas M. Barnes1, Camilla Tornoe3, Kazuhiko Matsuda3, Joohong Ahnn4, Andrew Fire4, John E. Sulston1, Eric A. Barnard2, David B. Sattelle3, and James A. Lewis5

1 Laboratory of Molecular Biology and 2 Molecular Neurobiology Unit, Medical Research Council Centre, Cambridge CB2 2QH, United Kingdom, 3 The Babraham Institute Laboratory of Molecular Signalling, Department of Zoology, Cambridge CB2 3EJ, United Kingdom, 4 Department of Embryology, Carnegie Institute of Washington, Baltimore, Maryland 21210, 5 Division of Life Sciences, University of Texas at San Antonio, San Antonio, Texas 78249, and 6 Department of Pediatric Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts 02114

We show that three of the eleven genes of the nematode Caenorhabditis elegans that mediate resistance to the nematocide levamisole and to other cholinergic agonists encode nicotinic acetylcholine receptor (nAChR) subunits. unc-38 encodes an alpha  subunit while lev-1 and unc-29 encode non-alpha subunits. The nematode nAChR subunits show conservation of many mammalian nAChR sequence features, implying an ancient evolutionary origin of nAChR proteins. Expression in Xenopus oocytes of combinations of these subunits that include the unc-38 alpha  subunit results in levamisole-induced currents that are suppressed by the nAChR antagonists mecamylamine, neosurugatoxin, and d-tubocurarine but not alpha -bungarotoxin. The mutant phenotypes reveal that unc-38 and unc-29 subunits are necessary for nAChR function, whereas the lev-1 subunit is not. An UNC-29-GFP fusion shows that UNC-29 is expressed in body and head muscles. Two dominant mutations of lev-1 result in a single amino acid substitution or addition in or near transmembrane domain 2, a region important to ion channel conductance and desensitization. The identification of viable nAChR mutants in C. elegans provides an advantageous system in which receptor expression and synaptic targeting can be manipulated and studied in vivo.

Key words: acetylcholine receptor; levamisole resistance genes; receptor mutations; Caenorhabditis elegans; evolution; nematode, unc-29; unc-38; lev-1; transmembrane domain mutation; Xenopus oocyte expression; GFP; confocal microscopy; receptor localization




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