Nicotinic acetylcholine receptors (nAChRs) mediate the fast actions of acetylcholine (ACh) at the neuromuscular junction and at nerve-nerve synapses in the central nervous system. The subunit composition of these pentameric receptors has been established for adult (
a1(2)
b1ge) and embryonic (
a1(2)
b1gd) skeletal muscle of vertebrates. In the nervous system, only two classes of subunit are recognized (a and b) but multiple isoforms of both exist (
a2-9 and
b2-4) (Hucho et al., 1996). Receptors containing
a4b2 are abundant in the vertebrate brain and
a3b4-containing nAChRs are present in the autonomic ganglia. A subset of vertebrate neuronal a subunits (
a7-9) can form functional homomeric receptors in heterologous expression systems such as Xenopus oocytes. The
a7 subunit has been exploited extensively for functional analysis of site directed mutants. The discovery in C. elegans of a homomer forming subunit, Ce21 (Ballivet et al., 1996), offers opportunities to compare function and pharmacology of nematode and vertebrate nAChRs. The C. elegans Ce21 a subunit homomer is activated by ACh and nicotine (Ballivet et al., 1996) and we have shown it is also strongly activated by the potent amphibian toxin, Epibatidine, which is a full agonist. Differences have been observed between the anthelmintic pharmacology of an expressed C. elegans heteromeric receptor (Fleming et al., 1997) and Ce21. Levamisole is an open channel blocker for Ce21, but has been shown to be an agonist for UNC-38+LEV-1+UNC-29 heteromers. Actions of several cholinergic anthelmintics including morantel, pyrantel and oxantel have been studied on both Ce21 and
a7. Only oxantel was found to have an agonist effect. Of the others tested to date, all blocked responses to nicotine. Ivermectin (IVM), an anthelmintic which acts on L-glutamate gated chloride channels (L-GluRs) (Cully et al., 1994) was recently shown to act as a positive allosteric modulator of
a7 homomers (Krause et al., 1998). IVM was also found to interact with Ce21. Comparison of nematode and vertebrate nicotinic receptor pharmacology may facilitate the design of novel pest control agents with enhanced selectivity. The authors are indebted to Dr. Marc Ballivet for the provision of Ce21 and
a7 clones. Ballivet, M., Alliod, C., Bertrand, S., and Bertrand, D. (1996) J.Mol.Biol. 258, 261-269 Cully, D.F., Vassilatis, D.K., Liu, K.K.Paress, P.S., Van der Ploeg, L.H.T., Schaeffer, J.M. and Arena, J.P. (1994) Science 371 707-711 Hucho, F., Tsetlin, V.I. and Machold, J. (1996).Eur.J.Biochem. 239, 539-557 Fleming JT Squire MD Barnes TM Torn!e CT Matsuda K Sulston JE Barnard EA Sattelle DB & Lewis JT (1997) J Neurosci 17 5843-5857 Krause, R.M., Buisson, B., Bertrand, S., Corringer, P.J., Galzi, J.L., Changeux, J.P. and Bertrand, D. (1998) Mol.Pharmacol. 53, 283-294