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