Altered ivermectin pharmacology and defective visual system inDrosophilamutants for histamine receptor HCLB

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The Drosophila gene hclB encodes a histamine-gated chloride channel, which can be activated by the neurotoxin ivermectin when expressed in vitro. We have identified two novel hclB mutants, carrying either a missense mutation (P293S, allele hclBT1) or a putative null mutation (W111*, allele hclBT2), as well as a novel splice form of the gene. In survival studies, hclBT1 mutants were more sensitive to ivermectin than wild-type, whereas hclBT2 were more resistant. Electroretinogram recordings from the two mutants exhibited enlarged peak amplitudes of the transient components, indicating altered synaptic transmission between retinal photoneurons and their target cells. Ivermectin treatment severely affected or completely suppressed these transient components in an allele-specific manner. This suppression of synaptic signals by ivermectin was dose-dependent. These results identify HCLB as an important in vivo target for ivermectin in Drosophila melanogaster, and demonstrate the involvement of this protein in the visual pathway.

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