Invertebrate glutamate-gated chloride channel (GluCl)

Invertebrate glutamate-gated chloride channels (GluCls) are members of the Cys-loop ligand-gated ion channel superfamily, found exclusively in protostome invertebrates such as nematodes and arthropods [1, 10]. They function as inhibitory neurotransmitter receptors, where the binding of glutamate triggers the opening of a chloride-selective pore, leading to membrane hyperpolarization and the suppression of neuronal or muscular activity [2, 11]. This physiological role is critical for regulating essential behaviors like locomotion, feeding (pharyngeal pumping), and sensory processing in parasites and pests [1, 13]. Because GluCls are absent in vertebrates, they serve as highly selective and effective targets for antiparasitic and insecticidal agents [10, 13]. The most prominent class of drugs targeting these channels is the macrocyclic lactones, including ivermectin and milbemycin, which act as potent allosteric activators [9, 16]. These drugs bind to a site within the transmembrane domain, causing the channel to remain open and resulting in the flaccid paralysis and eventual death of the target organism [2, 12]. While these channels are vital for controlling diseases like river blindness and lymphatic filariasis, the emergence of drug resistance and the potential for neurotoxicity in hosts with compromised blood-brain barriers remain significant therapeutic challenges [12, 17].

Other names

Glutamate-gated chloride channelGluCl receptorInvertebrate inhibitory glutamate receptorH-receptorAvermectin-sensitive glutamate-gated chloride channel

Allosteric activation and potentiation of chloride ion conductance, leading to neuronal and muscular hyperpolarization and subsequent flaccid paralysis of the target organism.