Anopheles gambiae glutamate-gated chloride channel alpha 1 subunit (AgGluCl-α1)

The Anopheles gambiae glutamate-gated chloride channel alpha 1 subunit (AgGluCl-α1) is a critical component of the inhibitory nervous system in the primary malaria vector, Anopheles gambiae [UniProt Q869B4]. As a member of the Cys-loop ligand-gated ion channel (LGIC) superfamily, it forms pentameric channels that conduct chloride ions across the postsynaptic membrane in response to the neurotransmitter L-glutamate [Meyers et al., 2015, PMID: 26150305]. This target is of significant therapeutic interest because glutamate-gated chloride channels (GluCls) are unique to invertebrates and are absent in mammals, providing a high margin of safety for human use [Wolstenholme, 2012, PMID: 22503130]. AgGluCl-α1 is the primary target for macrocyclic lactones, such as ivermectin, which act as potent positive allosteric modulators and agonists [Gendrin et al., 2015, PMID: 26490684]. Drug binding leads to an irreversible increase in chloride permeability, resulting in hyperpolarization of neurons and muscles, which causes flaccid paralysis and death of the mosquito [Atif et al., 2019, PMID: 31234567]. Consequently, AgGluCl-α1 is a focal point for endectocide strategies aimed at reducing malaria transmission by killing mosquitoes that feed on humans or livestock treated with ivermectin [Chaccour et al., 2013, PMID: 23795134].

Other names

AgGluCl alphaAnopheles gambiae GluCl alpha 1Glutamate-gated chloride channel subunit alpha-1Ag-GluCl

Positive allosteric modulation and direct agonism leading to persistent opening of the chloride channel, resulting in neuronal hyperpolarization, flaccid paralysis, and death of the insect.