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PMID:19675228

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Citation

Tanis, JE, Bellemer, A, Moresco, JJ, Forbush, B and Koelle, MR (2009) The potassium chloride cotransporter KCC-2 coordinates development of inhibitory neurotransmission and synapse structure in Caenorhabditis elegans. J. Neurosci. 29:9943-54

Abstract

Chloride influx through GABA-gated chloride channels, the primary mechanism by which neural activity is inhibited in the adult mammalian brain, depends on chloride gradients established by the potassium chloride cotransporter KCC2. We used a genetic screen to identify genes important for inhibition of the hermaphrodite-specific motor neurons (HSNs) that stimulate Caenorhabditis elegans egg-laying behavior and discovered mutations in a potassium chloride cotransporter, kcc-2. Functional analysis indicates that, like mammalian KCCs, C. elegans KCC-2 transports chloride, is activated by hypotonic conditions, and is inhibited by the loop diuretic furosemide. KCC-2 appears to establish chloride gradients required for the inhibitory effects of GABA-gated and serotonin-gated chloride channels on C. elegans behavior. In the absence of KCC-2, chloride gradients appear to be altered in neurons and muscles such that normally inhibitory signals become excitatory. kcc-2 is transcriptionally upregulated in the HSN neurons during synapse development. Loss of KCC-2 produces a decrease in the synaptic vesicle population within mature HSN synapses, which apparently compensates for a lack of HSN inhibition, resulting in normal egg-laying behavior. Thus, KCC-2 coordinates the development of inhibitory neurotransmission with synapse maturation to produce mature neural circuits with appropriate activity levels.

Links

PubMed PMC2737711 Online version:10.1523/JNEUROSCI.1989-09.2009

Keywords

Animals; Caenorhabditis elegans/physiology; Caenorhabditis elegans Proteins/metabolism; Chlorides/metabolism; Furosemide/pharmacology; Hypotonic Solutions; Motor Neurons/physiology; Muscles/physiology; Mutation; Receptors, G-Protein-Coupled/metabolism; Sequence Homology; Sexual Behavior, Animal/physiology; Sodium Potassium Chloride Symporter Inhibitors/pharmacology; Symporters/antagonists & inhibitors; Symporters/genetics; Symporters/metabolism; Synapses/physiology; Synaptic Transmission/physiology; Synaptic Vesicles/physiology; Up-Regulation

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

CAEEL:C0KDV0

enables

GO:0015379: potassium:chloride symporter activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

CAEEL:C0KDV0

involved_in

GO:0006813: potassium ion transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:C0KDV0

involved_in

GO:0006821: chloride transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:G5EEC9

enables

GO:0015379: potassium:chloride symporter activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

CAEEL:G5EEC9

involved_in

GO:0006813: potassium ion transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:G5EEC9

involved_in

GO:0006821: chloride transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:H2KZC2

enables

GO:0015379: potassium:chloride symporter activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

CAEEL:H2KZC2

involved_in

GO:0006813: potassium ion transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:H2KZC2

involved_in

GO:0006821: chloride transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:H2KZC3

enables

GO:0015379: potassium:chloride symporter activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

CAEEL:H2KZC3

involved_in

GO:0006813: potassium ion transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

CAEEL:H2KZC3

involved_in

GO:0006821: chloride transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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