GABA (γ-aminobutyric acid) is a classical inhibitory neurotransmitter, although it has been suggested that it might mediate excitation in some adult neurons. Beg and Jorgensen, writing in Nature Neuroscience, have characterized an unusual GABA receptor that is selective for cations rather than anions, giving it an excitatory effect.
The idea that GABA can be excitatory rather than inhibitory is not new — during development, for example, intracellular chloride levels are so high that activation of GABA receptors causes depolarization when Cl− ions flow out of the cell. However, in adult nervous systems, depolarization by activation of GABA receptors would require either an effect mediated by bicarbonate efflux, as in some hippocampal neurons, or a cation-selective GABA-gated ion channel. The latter has now been characterized for the first time, in the nematode Caenorhabditis elegans.
The enteric muscles in C. elegans contract in response to GABA release from a particular pair of motor neurons, indicating that GABA might have an excitatory effect on these muscles. Beg and Jorgensen investigated mutants in which the enteric muscles failed to contract and found one, the exp-1 mutant, in which the mutated gene was homologous to ligand-gated ion channel subunits. The EXP-1 protein was localized to sites that seemed to be neuromuscular junctions on the enteric muscles.
Further characterization showed that EXP-1 was similar to ionotropic GABA receptors in all domains except for the pore-forming domain, which confers ion specificity on the channel. When EXP-1 was expressed in Xenopus laevis oocytes, treatment with GABA evoked current flow with a reversal potential near 0 mV. This reversal potential, and the fact that the current did not depend on the presence of Cl− ions in the medium, indicated that EXP-1 might be a cation channel.
By testing the current–voltage relationships with different media, the authors determined that EXP-1 is permeable to monovalent cations such as Na+ and K+, but not to divalent cations. Receptors like EXP-1 could mediate the excitatory effects of GABA in other invertebrates, which have been suggested to result from the presence of GABA-gated cation channels, although there is less evidence for a similar mechanism in vertebrates.
ORIGINAL RESEARCH PAPER
Beg, A. A. & Jorgensen, E. M. EXP-1 is an excitatory GABA-gated cation channel. Nature Neurosci. 12 October 2003 (10.1038/nn1136)
Ben-Ari, Y. Excitatory actions of GABA during development: the nature of the nurture. Nature Rev. Neurosci. 3, 728–739 (2002)
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Jones, R. An exciting GABA receptor. Nat Rev Neurosci 4, 937 (2003). https://doi.org/10.1038/nrn1290