Two types of chloride transporters are required for GABA A 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.