Pharmacological characterization of the excitatory 'Cys-loop' GABA receptor family in Caenorhabditis elegans.

BACKGROUND AND PURPOSE

Ionotropic GABA receptors are evolutionarily conserved proteins that mediate cellular and network inhibition in both vertebrates and invertebrates. A unique class of excitatory GABA receptors has been identified in several nematode species. Despite well-characterized functions in Caenorhabditis elegans, little is known about the pharmacology of the excitatory GABA receptors EXP-1 and LGC-35. Using a panel of compounds that differentially activate and modulate ionotropic GABA receptors, we investigated the agonist binding site and allosteric modulation of EXP-1 and LGC-35.

EXPERIMENTAL APPROACH

We used two-electrode voltage clamp recordings to characterize the pharmacological profile of EXP-1 and LGC-35 receptors expressed in Xenopus laevis oocytes.

KEY RESULTS

The pharmacology of EXP-1 and LGC-35 is different from that of GABA and GABA -ρ receptors. Both nematode receptors are resistant to the competitive orthosteric antagonist bicuculline and to classical ionotropic receptor pore blockers. The GABA -ρ specific antagonist, TPMPA, was the only compound tested that potently inhibited EXP-1 and LGC-35. Neurosteroids have minimal effects on GABA-induced currents, but ethanol selectively potentiates LGC-35.

CONCLUSIONS AND IMPLICATIONS

The pharmacological properties of EXP-1 and LGC-35 more closely resemble the ionotropic GABA -ρ family. However, EXP-1 and LGC-35 exhibit a unique profile that differs from vertebrate GABA and GABA -ρ receptors, insect GABA receptors and nematode GABA receptors. As a pair, EXP-1 and LGC-35 may be utilized to further understand the differential molecular mechanisms of agonist, antagonist and allosteric modulation at ionotropic GABA receptors and may aid in the design of new and more specific anthelmintics that target GABA neurotransmission.