Glutamate-gated chloride channel receptor (GluClR) (GluClR)

Glutamate-gated chloride channels (GluCls) are members of the Cys-loop ligand-gated ion channel superfamily, found exclusively in protostome invertebrates such as insects, acarines (ticks and mites), and nematodes (Wolstenholme, 2012). They function as inhibitory receptors that, upon activation by the neurotransmitter glutamate, allow the influx of chloride ions, leading to membrane hyperpolarization and the suppression of neuronal or muscular activity (AOP-Wiki, 2024). GluCls play critical roles in regulating locomotion, feeding, and sensory processing in these organisms (NIH, 2012). Because they are absent in vertebrates, they serve as highly selective and effective targets for a variety of antiparasitic and insecticidal agents, most notably the macrocyclic lactones like ivermectin (RCSB PDB, 2015). These drugs typically act as potent allosteric agonists or positive modulators, causing irreversible channel opening that results in flaccid paralysis and death of the parasite or pest (NIH, 2019). However, the emergence of resistance through target-site mutations and the need for high selectivity over mammalian GABA and glycine receptors remain significant challenges in the development of new GluCl-targeting compounds (NIH, 2025).

Other names

GluClGluClRGlutamate-gated chloride channelH-receptorCys-loop ligand-gated chloride channel

Macrocyclic lactones (e.g., ivermectin) act as allosteric agonists or positive allosteric modulators that bind to the transmembrane domain, inducing a stable open state of the channel, leading to persistent chloride influx and hyperpolarization (AOP-Wiki, 2024). Phenylpyrazoles (e.g., fipronil) and organochlorines (e.g., lindane) act as non-competitive antagonists or pore blockers, inhibiting the inhibitory effect of glutamate and leading to hyperexcitability (NIH, 2012).