An ivermectin-sensitive glutamate-gated chloride channel subunit from Dirofilaria immitis.

Abstract

Dirofilaria immitis is a filarial nematode that infects dogs and causes cardiopulmonary disease. The most effective way of controlling the infection is by chemoprophylaxis, using members of the avermectin/milbemycin (A/M) class of anthelmintics, which includes ivermectin; these drugs act at invertebrate glutamate-gated chloride channels (GluCl). We have cloned two cDNAs encoding D. immitis GluCl subunits and demonstrated that at least one may be an important molecular target for the A/Ms in vivo. The subunits are orthologues of the alternatively spliced GluClalpha3A and alpha3B subunits (encoded by the avr-14 gene) previously identified in Caenorhabditis elegans and in Haemonchus contortus. Although the alternative splicing of avr-14 is conserved across the species, the processing of the mature GluClalpha3A mRNA differs in D. immitis compared to C. elegans and H. contortus. Two-electrode voltage clamp recordings were made from Xenopus oocytes injected with subunit-specific cRNAs. The DiGluClalpha3B subunit formed channels that were gated by L-glutamate (1-100 mM) and ivermectin (1 microM). Oocytes injected with DiGluClalpha3A cRNA failed to respond to L-glutamate. The qualitative responses obtained were consistent with the pharmacology observed for the GluClalpha3 subunits from C. elegans and H. contortus.

• Authors: Darran M Yates, Adrian J Wolstenholme
• Journal: International journal for parasitology (Int J Parasitol) Vol. 34 Issue 9 Pg. 1075-81 (Aug 2004) ISSN: 0020-7519 [Print] England
• PMID: 15313134 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chloride Channels
• Filaricides
• glutamate-gated chloride channels
• Ivermectin

Topics

• Alternative Splicing
• Amino Acid Sequence
• Animals
• Chloride Channels (drug effects, metabolism)
• Dirofilaria immitis (drug effects, genetics)
• Filaricides (pharmacology)
• Ivermectin (pharmacology)
• Molecular Sequence Data
• Oocytes (metabolism)
• Patch-Clamp Techniques
• Sequence Alignment
• Xenopus (metabolism)