Two types of chloride transporters are required for GABAA receptor-mediated inhibition in C. elegans

Chloride influx through GABA-gated Cl- channels, the principal mechanism for inhibiting neural activity in the brain, requires a Cl- gradient established in part by K+-Cl- cotransporters (KCCs). We screened for Caenorhabditis elegans mutants defective for inhibitory neurotransmission and identified mutations in ABTS-1, a Na+ -driven Cl--HCO3- exchanger that extrudes chloride from cells, like KCC-2, but also alkalinizes them. While animals lacking ABTS-1 or the K+-Cl- cotransporter KCC-2 display only mild behavioural defects, animals lacking both Cl- extruders are paralyzed. This is apparently due to severe disruption of the cellular Cl- gradient such that Cl- flow through GABA-gated channels is reversed and excites rather than inhibits cells. Neuronal expression of both transporters is upregulated during synapse development, and ABTS-1 expression further increases in KCC-2 mutants, suggesting regulation of these transporters is coordinated to control the cellular Cl- gradient. Our results show that Na+ -driven Cl--HCO3- exchangers function with KCCs in generating the cellular chloride gradient and suggest a mechanism for the close tie between pH and excitability in the brain. The EMBO Journal (2011) 30, 1852-1863. doi:10.1038/emboj.2011.83; Published online 22 March 2011