Molecular biology and electrophysiology of glutamategated chloride channels of invertebrates

Cully, Doris; Wilkinson, Hilary A.; Vassilatis, Demetrios K.; Etter, Adrian; Arena, Joseph P.

doi:10.1017/s0031182000077970

Cited by 89 publications

(58 citation statements)

References 58 publications

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“…GluCl channels are proteins with interesting pharmacological properties (36). Understanding the physiology of the GluCls can provide insight into mechanisms of anthelmintic and insecticide resistance (37).…”

Section: Chromosomal Mapping Of Glucl␣ and Glucl␤ Genes-thementioning

confidence: 99%

Genetic and Biochemical Evidence for a Novel Avermectin-sensitive Chloride Channel in Caenorhabditis elegans

Vassilatis¹,

Arena²,

Plasterk³

et al. 1997

Journal of Biological Chemistry

117

108

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Avermectins are a class of macrocyclic lactones that is widely used in crop protection and to treat helminth infections in man and animals. Two complementary DNAs (GluCl␣ and GluCl␤) encoding chloride channels that are gated by avermectin and glutamate, respectively, were isolated from Caenorhabditis elegans. To study the role of these subunits in conferring avermectin sensitivity we isolated a mutant C. elegans strain with a Tc1 transposable element insertion that functionally inactivated the GluCl␣ gene (GluCl␣::Tc1). GluCl␣::Tc1 animals exhibit a normal phenotype including typical avermectin sensitivity. Xenopus oocytes expressing GluCl␣::Tc1 strain mRNA elicited reduced amplitude avermectin and glutamate-dependent chloride currents. Avermectin binding assays in GluCl␣::Tc1 strain membranes showed the presence of high affinity binding sites, with a reduced B max . These experiments suggest that GluCl␣ is a target for avermectin and that additional glutamate-gated and avermectinsensitive chloride channel subunits exist in C. elegans. We isolated a cDNA (GluCl␣2) encoding a chloride channel that shares 75% amino acid identity with GluCl␣. This subunit forms homomeric channels that are gated irreversibly by avermectin and reversibly by glutamate. GluCl␣2 coassembles with GluCl␤ to form heteromeric channels that are gated by both ligands. The presence of subunits related to GluCl␣ may explain the low level and rarity of target site involvement in resistance to the avermectin class of compounds.

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Section: Chromosomal Mapping Of Glucl␣ and Glucl␤ Genes-thementioning

confidence: 99%

Genetic and Biochemical Evidence for a Novel Avermectin-sensitive Chloride Channel in Caenorhabditis elegans

Vassilatis¹,

Arena²,

Plasterk³

et al. 1997

Journal of Biological Chemistry

117

108

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“…In addition, there is a single ␤ subunit, encoded by glc-2, which responds to glutamate, but not ivermectin, in vitro (Cully et al, 1994). The glc-4 gene has not yet been successfully functionally expressed (Cully et al, 1996b) but is somewhat divergent in sequence from the others and may represent a third subunit class. In C. elegans, avr-14 and -15 are widely expressed in the nervous system (Dent et al, 1997(Dent et al, , 2000, whereas glc-2 expression is confined to pharyngeal muscle (Laughton et al, 1997b).…”

mentioning

confidence: 99%

Distribution of glutamate‐gated chloride channel subunits in the parasitic nematode Haemonchus contortus

Portillo

Jagannathan

Wolstenholme

2003

J of Comparative Neurology

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Glutamate-gated chloride channels (GluCl) are related to gamma-aminobutyric acid-A (GABA(A)) receptors and are the target sites for the avermectin/milbemycin (A/M) anthelmintics, drugs that cause paralysis of the somatic and pharyngeal muscles in nematodes. We have previously identified four GluCl subunits, HcGluClalpha, HcGluClbeta, HcGluClalpha3A, and HcGluClalpha3B from the sheep parasite Haemonchus contortus. We raised specific antisera against all of these subunits and used them in immunofluorescence experiments on adult parasites. All of the subunits were expressed in the motor nervous system, especially motor neuron commissures. Double-immunostaining experiments suggested that HcGluClalpha and HcGluClbeta were expressed on the same commissures; these were also stained with an anti-GABA antibody, suggesting that they may be inhibitory motor neurons. The HcGluClbeta subunit was also detected in lateral and sublateral nerve cords. The HcGluClalpha3A and -B subunits, products of an alternatively spliced gene, were expressed in different neurons. We found HcGluClalphaA in a pair of sensory, possibly amphid, neurons in the head, in addition to the motor neuron commissures. HcGluClalpha3B was detected in three cell bodies, probably of pharyngeal neurons, and to ventral and lateral cords. These results indicate that the GluCl are widely distributed in the H. contortus nervous system and suggest that they have critical roles controlling locomotion, pharyngeal function, and possibly sensory processing in parasitic nematodes. They also provide an explanation for the observed effects of the A/M anthelmintics.

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“…The activity of GABA finds only in the CNS and it does not readily cross the blood-brain barrier (Merck manual 11th edition). Avermectin induces paralysis via glutamate-gated Cl-channels which are only present in invertebrates (Arena et al, 1995;Cully et al, 1996). Avermectins have the affinity with GABA receptors in invertebrate receptors is about one hundredfold higher than the mammalian brain (Schaeffer and Haines, 1989).…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Management of Ivermectin Toxicity in a Calf: A Case Report

Patel¹,

Patel²,

Bhatt³

et al. 2018

Int.J.Curr.Microbiol.App.Sci

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Molecular biology and electrophysiology of glutamategated chloride channels of invertebrates

Cited by 89 publications

References 58 publications

Genetic and Biochemical Evidence for a Novel Avermectin-sensitive Chloride Channel in Caenorhabditis elegans

Genetic and Biochemical Evidence for a Novel Avermectin-sensitive Chloride Channel in Caenorhabditis elegans

Distribution of glutamate‐gated chloride channel subunits in the parasitic nematode Haemonchus contortus

Therapeutic Management of Ivermectin Toxicity in a Calf: A Case Report

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