The Kainate Receptor Subunit GluK2 Interacts With KCC2 to Promote Maturation of Dendritic Spines

Kesaf, Sebnem; Khirug, Stanislav; Dinh, Emilie Hoang; Garcia, Marta Saez; Soni, Shetal; Orav, Ester; Delpire, Eric; Taira, Tomi; Lauri, Sari E.; Rivera, Claudio

doi:10.3389/fncel.2020.00252

Cited by 16 publications

(21 citation statements)

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“…KCC2 physically interacts with a variety of membrane proteins, including the GluK2 subunit of kainate receptors [86,87] and its auxiliary subunit Neto2 [88], Task-3 (KCNK9) leak potassium channels [89], and GABA B receptors [90], adding to the variety of ways in which KCC2 can influence synaptic function and neuronal excitability. KCC2 also interacts with the Na-K-ATPase…”

Section: Structural Role Of Kcc2 In the Generation And Function Of Dendritic Spinesmentioning

confidence: 99%

The Multifaceted Roles of KCC2 in Cortical Development

Virtanen

Uvarov

Mavrović

et al. 2021

Trends in Neurosciences

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KCC2, best known as the neuron-specific chloride-extruder that sets the strength and polarity of GABAergic currents during neuronal maturation, is a multifunctional molecule that can regulate cytoskeletal dynamics via its C-terminal domain (CTD). We describe the molecular and cellular mechanisms involved in the multiple functions of KCC2 and its splice variants, ranging from developmental apoptosis and the control of early network events to the formation and plasticity of cortical dendritic spines. The versatility of KCC2 actions at the cellular and subcellular levels is also evident in mature neurons during plasticity, disease, and aging. Thus, KCC2 has emerged as one of the most important molecules that shape the overall neuronal phenotype. KCC2 in the Fundamental Machinery Underlying Neuronal Development, Signaling, and StructureFast synaptic transmission relies on ion fluxes through ligand-gated ion channels. Although the default state of a cell is to have a high intracellular chloride concentration ([Cl − ] i ), mature neurons in the CNS have evolved a unique ability to maintain a low [Cl − ] i , which is needed for the generation of hyperpolarizing Cl − currents across GABA A and glycine receptors (GABA A Rs and GlyRs) [1]. This specialization comes at a high energy cost [2], and is brought about by upregulation of the neuron-specific K-Cl cotransporter KCC2 during neuronal maturation [1,3,4]. KCC2 belongs to the evolutionarily ancient family of SLC12 cation/chloride cotransporters (CCCs) (Box 1; for KCCs and NKCCs, see Glossary) that have their roots in a single gene in Archaea, from which numerous duplication events in both archaeans and eukaryotes have led to the divergence and neofunctionalization of the paralogous CCC subfamilies [5]. Possibly because of a primordial role in cellular volume regulation, CCCs have evolved to communicate with the actin cytoskeleton. Indeed, KCC2 has emerged as an important player in controlling actin dynamics during neuronal development and plasticity [6][7][8][9].The functional upregulation of KCC2-mediated K-Cl cotransport in hippocampal and neocortical neurons underlies the hyperpolarizing shift in GABAergic currents which takes place postnatally in rats and mice [3], but it has become clear that KCC2 is expressed at low but functionally significant levels pre-and perinatally. KCC2 acts in an ion transport-independent manner as an antiapoptotic factor in projection neurons in the prenatal mouse neocortex [10]; in the perinatal mouse and rat hippocampus transport-functional KCC2 decreases the depolarizing driving force of GABA A R-mediated currents (DF GABA ), thereby influencing spontaneous network events at their developmental onset [11].In this review we highlight the developmental paths from KCC2 protein expression to its multiple functions, and discuss the wide variety of post-translational mechanisms which control these phenomena. The versatility of KCC2 regulation at the cellular and subcellular levels is also evident in mature neurons during plasticity, disease,...

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Section: Structural Role Of Kcc2 In the Generation And Function Of Dendritic Spinesmentioning

confidence: 99%

The Multifaceted Roles of KCC2 in Cortical Development

Virtanen

Uvarov

Mavrović

et al. 2021

Trends in Neurosciences

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“…The 4.1N–AMPAR bindings may not simply explain the AMPARs’ recruitment activity to synapses. 4.1N interacts with various proteins that are important for maintaining a balance in the dynamics of AMPARs trafficking through 4.1N ( Chevy et al, 2015 ; Kesaf et al, 2020 ). The GluK2 KAR subunits, KCC2 and CAM 1, are 4.1N-interacting proteins.…”

Section: 1n In the Nerve Systemmentioning

confidence: 99%

“…The GluK2 KAR subunits, KCC2 and CAM 1, are 4.1N-interacting proteins. KCC2 also directly binds to GluK2 ( Kesaf et al, 2020 ). In KCC2-deficient neurons, impaired trafficking activity of AMPARs to synapses is documented ( Gauvain et al, 2011 ; Fiumelli et al, 2013 ; Chevy et al, 2015 ), which is the downstream role of KCC2 in the spine maturation ( Kesaf et al, 2020 ).…”

Section: 1n In the Nerve Systemmentioning

confidence: 99%

“…KCC2 also directly binds to GluK2 ( Kesaf et al, 2020 ). In KCC2-deficient neurons, impaired trafficking activity of AMPARs to synapses is documented ( Gauvain et al, 2011 ; Fiumelli et al, 2013 ; Chevy et al, 2015 ), which is the downstream role of KCC2 in the spine maturation ( Kesaf et al, 2020 ). On the other hand, GluK2 deficiency leads to a significant change in subcellular distribution of KCC2 and reduction of GluR2 ( Kesaf et al, 2020 ).…”

Section: 1n In the Nerve Systemmentioning

confidence: 99%

“…In KCC2-deficient neurons, impaired trafficking activity of AMPARs to synapses is documented ( Gauvain et al, 2011 ; Fiumelli et al, 2013 ; Chevy et al, 2015 ), which is the downstream role of KCC2 in the spine maturation ( Kesaf et al, 2020 ). On the other hand, GluK2 deficiency leads to a significant change in subcellular distribution of KCC2 and reduction of GluR2 ( Kesaf et al, 2020 ). 4.1N expression is significantly downregulated in GluK2−/− mice ( Copits and Swanson, 2013 ) and cultured hippocampal neurons transduced with GluK2 shRNA ( Kesaf et al, 2020 ).…”

Section: 1n In the Nerve Systemmentioning

confidence: 99%

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4.1N-Mediated Interactions and Functions in Nerve System and Cancer

Yang

Liu

Wang

2021

Front. Mol. Biosci.

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Scaffolding protein 4.1N is a neuron-enriched 4.1 homologue. 4.1N contains three conserved domains, including the N-terminal 4.1-ezrin-radixin-moesin (FERM) domain, internal spectrin–actin–binding (SAB) domain, and C-terminal domain (CTD). Interspersed between the three domains are nonconserved domains, including U1, U2, and U3. The role of 4.1N was first reported in the nerve system. Then, extensive studies reported the role of 4.1N in cancers and other diseases. 4.1N performs numerous vital functions in signaling transduction by interacting, locating, supporting, and coordinating different partners and is involved in the molecular pathogenesis of various diseases. In this review, recent studies on the interactions between 4.1N and its contactors (including the α7AChr, IP3R1, GluR1/4, GluK1/2/3, mGluR8, KCC2, D2/3Rs, CASK, NuMA, PIKE, IP6K2, CAM 1/3, βII spectrin, flotillin-1, pp1, and 14-3-3) and the 4.1N-related biological functions in the nerve system and cancers are specifically and comprehensively discussed. This review provides critical detailed mechanistic insights into the role of 4.1N in disease relationships.

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Kainate receptors GluK1 and GluK2 differentially regulate synapse morphology

Duan

Tang

Jia

et al. 2022

Synapse

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The regulation of dendritic spine morphology is a critical aspect of neuronal network refinement during development and modulation of neurotransmission. Previous studies revealed that glutamatergic transmission plays a central role in synapse development. AMPA receptors and NMDA receptors regulate spine morphology in an activity dependent manner. However, whether and how Kainate receptors (KARs) regulate synapse development remains poorly understood. In this study, we found that GluK1 and GluK2 may play distinct roles in synapse development. In primary cultured hippocampal neurons, we found overexpression of the calcium-permeable GluK2(Q) receptor variant increased spine length and spine head area compared to overexpression of the calcium-impermeable GluK2(R) variant or EGFP transfected, control neurons, indicating that Q/R editing may play a role in GluK2 regulation of synapse development. Intriguingly, neurons transfected with GluK1(Q) showed decreased spine length and spine head area, while the density of dendritic spines was increased, suggesting that GluK1(Q) and GluK2(Q) have different effects on synaptic development. Swapping the critical domains between GluK2 and GluK1 demonstrated the N-terminal domain (NTD) is responsible for the different effects of GluK1 and GluK2. In conclusion, Kainate receptors GluK1 and GluK2 have distinct roles in regulating spine morphology and development, a process likely relying on the NTD.

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The Kainate Receptor Subunit GluK2 Interacts With KCC2 to Promote Maturation of Dendritic Spines

Cited by 16 publications

References 50 publications

The Multifaceted Roles of KCC2 in Cortical Development

The Multifaceted Roles of KCC2 in Cortical Development

4.1N-Mediated Interactions and Functions in Nerve System and Cancer

Kainate receptors GluK1 and GluK2 differentially regulate synapse morphology

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