Invertebrate L-glutamate-gated chloride channel (GluCl)

The invertebrate L-glutamate-gated chloride channel (GluCl) is a member of the Cys-loop family of ligand-gated ion channels, found exclusively in protostome invertebrates such as nematodes and arthropods (Wolstenholme, 2012). It mediates fast inhibitory neurotransmission by allowing the influx of chloride ions upon activation by L-glutamate, leading to membrane hyperpolarization and suppression of electrical activity (Hibbs & Gouaux, 2011). Because GluCls are absent in vertebrates, they serve as a critical selective target for several classes of antiparasitic drugs and insecticides, providing a high therapeutic index (Cully et al., 1994). Macrocyclic lactones, such as ivermectin, bind allosterically to these channels to cause prolonged opening, which results in the flaccid paralysis and death of parasites like heartworms and lice (AOPWiki, AOP113). Other compounds, including fipronil and the isoxazoline class, target these channels as antagonists to disrupt the nervous system of ectoparasites. Understanding GluCl structure and function is essential for managing parasitic diseases in veterinary and human medicine and for addressing the growing challenge of drug resistance in global health (UniProtKB, G5EBR3).

Other names

Glutamate-gated chloride channelGluCl receptorGluClRH-receptorAvermectin-sensitive glutamate-gated chloride channel

Macrocyclic lactones (e.g., ivermectin) act as potent positive allosteric modulators and agonists that bind to the transmembrane domain of the channel, stabilizing the open state and leading to persistent chloride influx, hyperpolarization, and flaccid paralysis of the parasite (Hibbs & Gouaux, 2011; Wolstenholme, 2012). Conversely, phenylpyrazoles (e.g., fipronil) and isoxazolines (e.g., afoxolaner) act as non-competitive antagonists that block the channel pore, causing hyperexcitation and death (Casida & Durkin, 2013).