Abstract
Glutamate-gated chloride (GluCl) channels are the site of action of the anthelmintic ivermectin. Previously, the Xenopus laevis oocyte expression system has been used to characterize GluCl channels cloned from Caenorhabditis elegans. However, information on the native, pharmacologically relevant receptors is lacking. Here, we have used a quantitative pharmacological approach and intracellular recording techniques ofC. elegans pharynx to characterize them. The glutamate response was a rapidly desensitizing, reversible, chloride-dependent depolarization (EC50 = 166 μM), only weakly antagonized by picrotoxin. The order of potency of agonists was ibotenate > l-glutamate > kainate = quisqualate. Ivermectin potently and irreversibly depolarized the muscle (EC50 = 2.7 nM). No further depolarization was seen with coapplication of maximal glutamate during the maximal ivermectin response, indicating that ivermectin depolarizes the muscle by the same ionic mechanism as glutamate (i.e., chloride). The potency of ivermectin on the pharynx was greater than at any of the GluCl subunits expressed in X. laevis oocytes. This effect of ivermectin was abolished in the mutant avr-15, which lacks a functional GluCl-α2 subunit. However, a chloride-dependent, nondesensitizing response to glutamate persisted. Therefore, the GluCl-α2 subunit confers ivermectin sensitivity and a high-affinity desensitizing glutamate response on the native pharyngeal GluCl receptor.
Footnotes
- Received October 19, 2000.
- Accepted January 19, 2001.
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Send reprint requests to: Dr. Lindy Holden-Dye, Centre for Neuroscience, University of Southampton, Bassett Crescent East, Southampton SO16 7PX, UK. E-mail: lmhd{at}soton.ac.uk
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·This work was supported in part by the University of Southampton, UK, and the Biotechnology and Biological Research Council UK Grant no. SO5805, and the Wessex Medical Trust.
- The American Society for Pharmacology and Experimental Therapeutics
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