PMID- 30570751
OWN - NLM
STAT- MEDLINE
DCOM- 20200709
LR  - 20231213
IS  - 1469-7793 (Electronic)
IS  - 0022-3751 (Print)
IS  - 0022-3751 (Linking)
VI  - 597
IP  - 6
DP  - 2019 Mar
TI  - Ionotropic and metabotropic kainate receptor signalling regulates Cl(-) 
      homeostasis and GABAergic inhibition.
PG  - 1677-1690
LID - 10.1113/JP276901 [doi]
AB  - KEY POINTS: Potassium-chloride co-transporter 2 (KCC2) plays a critical role in 
      regulating chloride homeostasis, which is essential for hyperpolarizing 
      inhibition in the mature nervous system. KCC2 interacts with many proteins 
      involved in excitatory neurotransmission, including the GluK2 subunit of the 
      kainate receptor (KAR). We show that activation of KARs hyperpolarizes the 
      reversal potential for GABA (E(GABA) ) via both ionotropic and metabotropic 
      signalling mechanisms. KCC2 is required for the metabotropic KAR-mediated 
      regulation of E(GABA) , although ionotropic KAR signalling can hyperpolarize 
      E(GABA) independent of KCC2 transporter function. The KAR-mediated 
      hyperpolarization of E(GABA) is absent in the GluK1/2(-/-) mouse and is 
      independent of zinc release from mossy fibre terminals. The ability of KARs to 
      regulate KCC2 function may have implications in diseases with disrupted 
      excitation: inhibition balance, such as epilepsy, neuropathic pain, autism 
      spectrum disorders and Down's syndrome. ABSTRACT: Potassium-chloride 
      co-transporter 2 (KCC2) plays a critical role in the regulation of chloride 
      (Cl(-) ) homeostasis within mature neurons. KCC2 is a secondarily active 
      transporter that extrudes Cl(-) from the neuron, which maintains a low 
      intracellular Cl(-) concentration [Cl(-) ]. This results in a hyperpolarized 
      reversal potential of GABA (E(GABA) ), which is required for fast synaptic 
      inhibition in the mature central nervous system. KCC2 also plays a structural 
      role in dendritic spines and at excitatory synapses, and interacts with 
      'excitatory' proteins, including the GluK2 subunit of kainate receptors (KARs). 
      KARs are glutamate receptors that display both ionotropic and metabotropic 
      signalling. We show that activating KARs in the hippocampus hyperpolarizes 
      E(GABA) , thus strengthening inhibition. This hyperpolarization occurs via both 
      ionotropic and metabotropic KAR signalling in the CA3 region, whereas it is 
      absent in the GluK1/2(-/-) mouse, and is independent of zinc release from mossy 
      fibre terminals. The metabotropic signalling mechanism is dependent on KCC2, 
      although the ionotropic signalling mechanism produces a hyperpolarization of 
      E(GABA) even in the absence of KCC2 transporter function. These results 
      demonstrate a novel functional interaction between a glutamate receptor and KCC2, 
      a transporter critical for maintaining inhibition, suggesting that the KAR:KCC2 
      complex may play an important role in excitatory:inhibitory balance in the 
      hippocampus. Additionally, the ability of KARs to regulate chloride homeostasis 
      independently of KCC2 suggests that KAR signalling can regulate inhibition via 
      multiple mechanisms. Activation of kainate-type glutamate receptors could serve 
      as an important mechanism for increasing the strength of inhibition during 
      periods of strong glutamatergic activity.
CI  - (c) 2018 The Authors. The Journal of Physiology (c) 2018 The Physiological Society.
FAU - Garand, Danielle
AU  - Garand D
AD  - Department of Cell and Systems Biology, University of Toronto, Toronto, ON, 
      Canada.
FAU - Mahadevan, Vivek
AU  - Mahadevan V
AUID- ORCID: 0000-0002-0805-827X
AD  - Department of Cell and Systems Biology, University of Toronto, Toronto, ON, 
      Canada.
FAU - Woodin, Melanie A
AU  - Woodin MA
AUID- ORCID: 0000-0003-2984-8630
AD  - Department of Cell and Systems Biology, University of Toronto, Toronto, ON, 
      Canada.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190121
PL  - England
TA  - J Physiol
JT  - The Journal of physiology
JID - 0266262
RN  - 0 (Chlorides)
RN  - 0 (Gluk1 kainate receptor)
RN  - 0 (Receptors, GABA)
RN  - 0 (Receptors, Kainic Acid)
RN  - 0 (Symporters)
SB  - IM
CIN - Epilepsy Curr. 2019 May-Jun;19(3):187-189. PMID: 31032637
MH  - Animals
MH  - CA1 Region, Hippocampal/cytology/metabolism/physiology
MH  - CA3 Region, Hippocampal/cytology/metabolism/physiology
MH  - Cells, Cultured
MH  - Chlorides/*metabolism
MH  - Female
MH  - Homeostasis
MH  - *Inhibitory Postsynaptic Potentials
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mossy Fibers, Hippocampal/metabolism/physiology
MH  - Pyramidal Cells/*metabolism/physiology
MH  - Receptors, GABA/*metabolism
MH  - Receptors, Kainic Acid/*metabolism
MH  - Symporters/metabolism
MH  - K Cl- Cotransporters
MH  - GluK2 Kainate Receptor
PMC - PMC6418771
OTO - NOTNLM
OT  - Chloride transport
OT  - GABA
OT  - KCC2
OT  - Kainate receptor
OT  - electrophysiology
OT  - hippocampus
OT  - ionotropic
OT  - metabotropic
EDAT- 2018/12/21 06:00
MHDA- 2020/07/10 06:00
PMCR- 2020/03/15
CRDT- 2018/12/21 06:00
PHST- 2018/07/31 00:00 [received]
PHST- 2018/12/19 00:00 [accepted]
PHST- 2018/12/21 06:00 [pubmed]
PHST- 2020/07/10 06:00 [medline]
PHST- 2018/12/21 06:00 [entrez]
PHST- 2020/03/15 00:00 [pmc-release]
AID - TJP13384 [pii]
AID - 10.1113/JP276901 [doi]
PST - ppublish
SO  - J Physiol. 2019 Mar;597(6):1677-1690. doi: 10.1113/JP276901. Epub 2019 Jan 21.