Mechanism of activity-dependent downregulation of the neuron-specific K-Cl cotransporter KCC2.
GABA-mediated fast-hyperpolarizing inhibition depends on extrusion of chloride by the neuron-specific K-Cl cotransporter, KCC2. Here we show that sustained interictal-like activity in hippocampal slices downregulates KCC2 mRNA and protein expression in CA1 pyramidal neurons, which leads to a reduced capacity for neuronal Cl- extrusion. This effect is mediated by endogenous BDNF acting on tyrosine receptor kinase B (TrkB), with down-stream cascades involving both Shc/FRS-2 (src homology 2 domain containing transforming protein/FGF receptor substrate 2) and PLCgamma (phospholipase Cgamma)-cAMP response element-binding protein signaling. The plasmalemmal KCC2 has a very high rate of turnover, with a time frame that suggests a novel role for changes in KCC2 expression in diverse manifestations of neuronal plasticity. A downregulation of KCC2 may be a general early response involved in various kinds of neuronal trauma.
Rivera
Claudio
C
Department of Biosciences, University of Helsinki, Helsinki, FIN-00014 Finland. Claudio.Rivera@helsinki.fi
Voipio
Juha
J
Thomas-Crusells
Judith
J
Li
Hong
H
Emri
Zsuzsa
Z
Sipilä
Sampsa
S
Payne
John A
JA
Minichiello
Liliana
L
Saarma
Mart
M
Kaila
Kai
K
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D019921:Biotinylation; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D066298:In Vitro Techniques; D008274:Magnesium / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D051966:Phospholipase C gamma; D010766:Phosphorylation / Q000187:drug effects; D017966:Pyramidal Cells / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020813:Receptor, trkB / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction / Q000502:physiology; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology; D010738:Type C Phospholipases / Q000378:metabolism; D000096922:K Cl- Cotransporters
D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D019208:Brain-Derived Neurotrophic Factor; D002712:Chlorides; D017362:Cyclic AMP Response Element-Binding Protein; D008274:Magnesium; D051966:Phospholipase C gamma; D012333:RNA, Messenger; D020813:Receptor, trkB; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D027981:Symporters; D010738:Type C Phospholipases; D000096922:K Cl- Cotransporters; C528034:Shc1 protein, mouse; C528035:Shc1 protein, rat