Glutamate-gated chloride channels

Abstract

Glutamate-gated chloride channels (GluCls) are found only in protostome invertebrate phyla but are closely related to mammalian glycine receptors. They have a number of roles in these animals, controlling locomotion and feeding and mediating sensory inputs into behavior. In nematodes and arthropods, they are targeted by the macrocyclic lactone family of anthelmintics and pesticides, making the GluCls of considerable medical and economic importance. Recently, the three-dimensional structure of a GluCl was solved, the first for any eukaryotic ligand-gated anion channel, revealing a macrocyclic lactone-binding site between the channel domains of adjacent subunits. This minireview will highlight some unique features of the GluCls and illustrate their contribution to our knowledge of the entire Cys loop ligand-gated ion channel superfamily.

FIGURE 1.

Transmitter-binding site residues of invertebrate 2-Cys loop ligand-gated anion channels. The binding loops are shown, as described (87), for examples of nematode and insect GluCls, insect HisCls and pHCl, and mollusk GluCls. Cel, C. elegans; Hco, H. contortus; Dmel, D. melanogaster; Aca, A. californica. Amino acid resides that make contacts with bound glutamate in the GluCl structure (87) are highlighted in red; where these are substituted in other channels, they are colored purple. The alignment was made using ClustalΩ.

FIGURE 2.

Role of GluCls in mediating sensory inputs in worms and flies. A, in C. elegans, GLC-3 is expressed on the AIY interneuron, outputs from which suppress the frequency of turns during locomotion (94). Glutamate released from either of the AWC and AFD sensory neurons will activate GLC-3-containing GluCls, inhibiting AIY and thus increasing the frequency of turns. AWC is an “odor-off” neuron inhibited by the presence of a volatile odor (59), so it will normally release glutamate and promote turning behavior. In the presence of the odor, glutamate release is prevented, and GluCl on AIY will not be activated, so turns will be inhibited, and the worm will tend to move toward the source of the odor. AFD is activated by temperature to release glutamate. In this case, an increase in temperature will cause inhibition of AIY via GluCls, and hence, the worm will tend to turn away. B, in Drosophila, GluClα is expressed on the LN_vS neurons (75), which mediate light avoidance behavior. This is driven by the light-induced release of acetylcholine (ACh) from the visual system. Early in the day, the dorsal clock neurons (DN_iS) do not release glutamate, and acetylcholine drives light avoidance behavior. At dusk, increased clock gene activity results in the release of glutamate from DN_iS, which activates GluCls on LN_vS and inhibits light avoidance.

FIGURE 3.

Mechanism by which ivermectin promotes opening of GluCl channels. Ivermectin binds between the M1 and M3 membrane-spanning domains of adjacent subunits and tends to push the membrane-spanning regions of the subunits apart, thus opening the channel (87). Contacts with the M2-M3 loop and other parts of the extracellular domain transmit the allosteric signal to the ligand-binding site. A, side view. B, top view. This figure has been reprinted by permission (87).