title: Two types of chloride transporters are required for GABA(A) receptor-mediated inhibition in C. elegans.
abstract: 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(-)-HCO(3)(-) 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(-)-HCO(3)(-) 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.
authors.affiliation: Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06520-8024, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Bellemer
authors.forename: Taku
authors.initials: T
authors.lastname: Hirata
authors.forename: Michael F
authors.initials: MF
authors.lastname: Romero
authors.forename: Michael R
authors.initials: MR
authors.lastname: Koelle
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D027321:Anion Transport Proteins / Q000235:genetics* / Q000378:metabolism; D001921:Brain / Q000378:metabolism*; D017173:Caenorhabditis elegans / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism*; D004594:Electrophysiology; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D006863:Hydrogen-Ion Concentration; D008853:Microscopy; D009043:Motor Activity / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D010957:Plasmids / Q000235:genetics; D011963:Receptors, GABA-A / Q000378:metabolism*; D027981:Symporters / Q000235:genetics* / Q000378:metabolism; D019076:Transgenes / Q000235:genetics; D014981:Xenopus; D000096922:K Cl- Cotransporters
chemical_list: D027321:Anion Transport Proteins; D029742:Caenorhabditis elegans Proteins; D002712:Chlorides; D011963:Receptors, GABA-A; D027981:Symporters; D000096922:K Cl- Cotransporters; C551533:ABTS-1 protein, C elegans