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

Andrew Bellemer, Taku Hirata, Michael F. Romero, Michael R. Koelle

Research output: Contribution to journalArticle

23 Scopus citations

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- -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.

Original languageEnglish (US)
Pages (from-to)1852-1863
Number of pages12
JournalEMBO Journal
Volume30
Issue number9
DOIs
StatePublished - May 4 2011

Keywords

  • C. elegans
  • GABA
  • chloride
  • transporter

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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