KCC2 regulates actin dynamics in dendritic spines via interaction with β-PIX

Llano, Olaya; Smirnov, Sergey V.; Soni, Shetal; Golubtsov, Andrey; Guillemin, Isabelle; Hotulainen, Pirta; Medina, Igor; Nothwang, Hans Gerd; Rivera, Claudio; Ludwig, Anastasia

doi:10.1084/jem.2127oia56

Cited by 26 publications

(60 citation statements)

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“…; Llano et al . ). It is responsible for maintaining a low intracellular chloride concentration by extruding chloride ions and, thus, producing a hyperpolarizing effect when GABA and glycine bind to their cognate receptors, resulting in inhibition (Rivera et al .…”

Section: Chloride Co‐transportersmentioning

confidence: 97%

Chloride co‐transporters as possible therapeutic targets for stroke

Baudel

Poole

Darlison

2016

Journal of Neurochemistry

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Stroke is one of the major causes of death and disability worldwide. The major type of stroke is an ischaemic one, which is caused by a blockage that interrupts blood flow to the brain. There are currently very few pharmacological strategies to reduce the damage and social burden triggered by this pathology. The harm caused by the interruption of blood flow to the brain unfolds in the subsequent hours and days, so it is critical to identify new therapeutic targets that could reduce neuronal death associated with the spread of the damage. Here, we review some of the key molecular mechanisms involved in the progression of neuronal death, focusing on some new and promising studies. In particular, we focus on the potential of the chloride co-transporter (CCC) family of proteins, mediators of the GABAergic response, both during the early and later stages of stroke, to promote neuroprotection and recovery. Different studies of CCCs during the chronic and recovery phases post-stroke reveal the importance of timing when considering CCCs as potential neuroprotective and/or neuromodulator targets. The molecular regulatory mechanisms of the two main neuronal CCCs, NKCC1 and KCC2, are further discussed as an indirect approach for promoting neuroprotection and neurorehabilitation following an ischaemic insult. Finally, we mention the likely importance of combining different strategies in order to achieve more effective therapies.

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Section: Chloride Co‐transportersmentioning

confidence: 97%

Chloride co‐transporters as possible therapeutic targets for stroke

Baudel

Poole

Darlison

2016

Journal of Neurochemistry

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“…and perfused transcardially with a solution of 4% paraformaldehyde supplemented with 4% sucrose in 0.1 M PBS, pH 7.4 (Santa Cruz Biotechnology, Dallas, TX, USA). After perfusion, each brain was immersed in 4% paraformaldehyde at 4 ° C, cryoprotected in ascending gradients (10,20, and 30%) of sucrose solutions, then frozen in precooled isopentane and stored at -80 ° C. Coronal sections (30-50 µm thick) of the somatosensory region were obtained using a cryostat, followed by immunostaining.…”

Section: Tissue Processingmentioning

confidence: 99%

“…KCC2 exports chloride ion (Cl -), while NKCC1 imports Cl -, resulting in neuronal excitability change and the alteration of GABAergic function. KCC2 also plays a role in neuronal migration during corticogenesis as well as regulating actin dynamics and the formation of dendritic spines [6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Distribution and Cellular Localization of KCC2 in the Ferret Neocortex

Djankpa¹,

Akinola

Juliano³

2018

Dev Neurosci

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KCC2 (a brain-specific potassium-chloride cotransporter) affects development of the cerebral cortex, including aspects of neuronal migration and cellular maturation and differentiation. KCC2 also modulates chloride homeostasis by influencing the switch of GABA from depolarizing in young neurons to hyperpolarizing in mature neurons. We describe the expression pattern, regional distribution, and cellular colocalization of KCC2 in the ferret cortex in normal kits and those treated with methylazoxymethanol acetate (MAM). We earlier developed a model of impaired cortical development by injecting MAM during mid-cortical gestation, which briefly interferes with neuronal production and additionally results in increased levels of KCC2 at P0. Using immunohistochemistry, we show a shift in KCC2 expression during development, being high in the subplate at P0, repositioning into a subtle laminar pattern in the neocortex at P7-P14, and becoming homogeneous at P35. KCC2 colocalizes with neuronal markers in the developing and mature cerebral cortex of normal ferrets and those treated with MAM, but shows a differential pattern of expression at different ages and locates in distinct cellular compartments during development. Subcellular localization shows that KCC2 predominantly situates in the membrane fraction of neocortical samples. These findings reveal that KCC2 colocalizes differentially with neurons and its expression pattern alters during development.

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“…, Llano et al . ), where it plays an important role in dendritic spine formation and maintenance, and influences AMPA receptor (AMPAR) content and diffusion out of the synapse (Li et al . , Gauvain et al .…”

Section: Introductionmentioning

confidence: 99%

“…, Llano et al . ). KCC2 has also been shown to physically interact with several excitatory receptors and proteins (Mahadevan et al .…”

Section: Introductionmentioning

confidence: 99%

Ionotropic and metabotropic kainate receptor signalling regulates Cl⁻ homeostasis and GABAergic inhibition

Garand

Mahadevan

Woodin

2019

The Journal of Physiology

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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 (EGABA) via both ionotropic and metabotropic signalling mechanisms. KCC2 is required for the metabotropic KAR‐mediated regulation of EGABA, although ionotropic KAR signalling can hyperpolarize EGABA independent of KCC2 transporter function. The KAR‐mediated hyperpolarization of EGABA 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 (EGABA), 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 EGABA, 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 EGABA 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.

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KCC2 regulates actin dynamics in dendritic spines via interaction with β-PIX

Cited by 26 publications

References 1 publication

Chloride co‐transporters as possible therapeutic targets for stroke

Chloride co‐transporters as possible therapeutic targets for stroke

Distribution and Cellular Localization of KCC2 in the Ferret Neocortex

Ionotropic and metabotropic kainate receptor signalling regulates Cl⁻ homeostasis and GABAergic inhibition

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KCC2 regulates actin dynamics in dendritic spines via interaction with β-PIX

Cited by 26 publications

References 1 publication

Chloride co‐transporters as possible therapeutic targets for stroke

Chloride co‐transporters as possible therapeutic targets for stroke

Distribution and Cellular Localization of KCC2 in the Ferret Neocortex

Ionotropic and metabotropic kainate receptor signalling regulates Cl− homeostasis and GABAergic inhibition

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Product

Resources

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Ionotropic and metabotropic kainate receptor signalling regulates Cl⁻ homeostasis and GABAergic inhibition