γ-Aminobutyric acid (GABA) is a well-known inhibitory neurotransmitter that can activate a family of ligand-gated chloride channels (GABAA receptors). However, in several systems such as crabs, snails, and the nematode Caenorhabditis elegans, there is evidence indicating an excitatory GABA response that is not due to changes in chloride conductance. Beg and Jorgensen cloned a gene (EXP-1) responsible for defecation defects due to loss of enteric muscle contraction in C. elegans. EXP-1 was expressed in two of the enteric muscles (intestine and anal depressor muscles) and appeared to be clustered at neuromuscular junctions. Expression was also present in several neurons. EXP-1 encoded a protein that could be classified as an ionotropic GABA receptor: EXP-1 has a conserved GABA-binding site, and its predicted membrane topology is similar to that of GABAA receptors. When expressed in Xenopus oocytes, EXP-1 produced an inward current when GABA was applied. Ion replacement studies and current-voltage analysis indicated that EXP-1 was permeable to monovalent cations (Na+, K+), not anions (Cl–) or divalent cations (Ba2+). Consistent with EXP-1's acting as a cation channel, residues in the predicted pore-forming M2 domain have the profile of a cationic selective channel. Thus, the GABA receptor family needs to be expanded to include excitatory cation channels, as well as the inhibitory anion channels.
A. A. Beg, E. M. Jorgensen, EXP-1 is an excitatory GABA-gated cation channel. Nat. Neurosci. 6, 1145-1152 (2003). [Online Journal]