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

The Glutamate-gated chloride channel receptor (GluCl) is a member of the Cys-loop superfamily of ligand-gated ion channels, uniquely expressed in invertebrates such as the nematode Caenorhabditis elegans [1][2]. These receptors are composed of alpha and beta subunits that form pentameric structures, mediating fast inhibitory neurotransmission by facilitating chloride ion influx upon activation by L-glutamate [2][3]. In C. elegans, GluCl receptors play a vital role in regulating essential behaviors, including locomotion and pharyngeal pumping, which is necessary for feeding [2]. They are the primary molecular target for macrocyclic lactone anthelmintics, most notably ivermectin, which binds to the transmembrane domain to act as a potent allosteric agonist [3][4]. This binding causes the channel to remain open, leading to prolonged hyperpolarization of nerve and muscle cells, resulting in flaccid paralysis and the eventual death of the parasite [4][5]. Since GluCl receptors are not found in mammals, they serve as a highly selective target for treating parasitic infections in humans and animals [1][5]. However, safety concerns exist regarding potential neurotoxicity if these drugs cross the blood-brain barrier and interact with vertebrate GABA or glycine receptors [4][5]. Sources: [1] Wolstenholme, A. J. (2012). Glutamate-gated chloride channels. BioEssays. https://doi.org/10.1002/bies.201100176 [2] Cully, D. F., et al. (1994). Cloning of an avermectin-sensitive glutamate-gated chloride channel from Caenorhabditis elegans. Nature. https://doi.org/10.1038/371707a0 [3] Hibbs, R. E., & Gouaux, E. (2011). Principles of activation and permeation in an anion-selective Cys-loop receptor. Nature. https://doi.org/10.1038/nature10139 [4] Lynagh, T., & Lynch, J. W. (2012). Ivermectin binding sites in human and invertebrate Cys-loop receptors. Trends in Pharmacological Sciences. https://doi.org/10.1016/j.tips.2012.03.002 [5] Yates, D. M., et al. (2003). The pharmacology of ivermectin and its target receptors. Pesticide Biochemistry and Physiology. https://doi.org/10.1016/S0048-3575(03)00031-3

Other names

Glutamate-gated chloride channelGluCl receptorAvermectin-sensitive glutamate-gated chloride channelGLC-1GLC-2GLC-3GLC-4AVR-14AVR-15HOR-2

Positive allosteric modulation and direct activation of the chloride channel, leading to persistent hyperpolarization and flaccid paralysis of the parasite.