KCC2 Interacts with the Dendritic Cytoskeleton to Promote Spine Development

Li, Hong; Khirug, Stanislav; Cai, Chunlin; Ludwig, Anastasia; Blaesse, Peter; Kolikova, Julia; Afzalov, Ramil; Coleman, Sarah K.; Lauri, Sari E.; Airaksinen, Matti S.; Keinänen, Kari; Khiroug, Leonard; Saarma, Märt; Kaila, Kai; Rivera, Claudio

doi:10.1016/j.neuron.2007.10.039

Cited by 264 publications

(395 citation statements)

References 58 publications

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“…However, KCC2 also plays an additional role in regulating neuronal morphology (5,31,32). We tested the possibility that disrupting the Neto2-KCC2 interaction also affects neuronal morphology by performing a Scholl analysis, and found no significant difference between the number of dendritic intersections between WT and Neto2 −/− neurons ( Fig.…”

Section: Resultsmentioning

confidence: 98%

“…KCC2 also interacts with a member of the Na + -K + -ATPase family, Atp1a2 (37); however, this regulation may be limited to the respiratory center of the brainstem (6), because neuronal expression of Atp1a2 dramatically decreases during maturation of the CNS (38). Last, KCC2 interacts to the cytoskeleton-associated protein 4.1N, but this interaction does not regulate KCC2-mediated Cl − extrusion, but rather functions to promote spine development (32). Thus, our data demonstrate the existence of a KCC2 interacting protein that is required for proper neuronal Cl − regulation in the mature CNS.…”

Section: Discussionmentioning

confidence: 99%

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Neto2 is a KCC2 interacting protein required for neuronal Cl ⁻ regulation in hippocampal neurons

Ivakine

Acton

Mahadevan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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KCC2 is a neuron-specific K + -Cl − cotransporter that is essential for Cl − homeostasis and fast inhibitory synaptic transmission in the mature CNS. Despite the critical role of KCC2 in neurons, the mechanisms regulating its function are not understood. Here, we show that KCC2 is critically regulated by the single-pass transmembrane protein neuropilin and tolloid like-2 (Neto2). Neto2 is required to maintain the normal abundance of KCC2 and specifically associates with the active oligomeric form of the transporter. Loss of the Neto2:KCC2 interaction reduced KCC2-mediated Cl − extrusion, resulting in decreased synaptic inhibition in hippocampal neurons. that makes fast GABA A Rmediated synaptic inhibition possible is maintained by the neuronspecific K + -Cl − cotransporter KCC2 (4), a member of the cationchloride cotransporter SLC12 gene family (5). KCC2 is essential for survival, as KCC2 knockout mice die immediately at birth due to respiratory failure (6). In the adult nervous system, decreased KCC2 expression correlates with neuropathic pain, spasticity following spinal cord injury, and epileptic seizures (5, 7-11).Based on the critical importance of KCC2 in the brain, an understanding of the mechanisms that promote and maintain KCC2 expression and efficacy is essential for designing therapeutic strategies to treat neurological disorders characterized by KCC2 dysfunction and the subsequent loss of inhibitory synaptic transmission. A major limitation in the development of these strategies is a lack of understanding regarding the cellular mechanisms regulating KCC2. In particular, KCC2 interacting proteins required for KCC2 transport and function in the mature CNS have not been identified, which represents a large gap in our fundamental knowledge regarding neuronal Cl − regulation and inhibitory synaptic transmission.Here, we identify neuropilin and tolloid like-2 (Neto2) as a KCC2 interacting protein in vivo and demonstrate that this interaction is required for normal neuronal Cl − homeostasis. Neto2 is a complement C1r/C1s, Uegf, Bmp1 (CUB) domain-containing transmembrane protein abundantly expressed in neurons (12), which is important for proper neurological function (13). CUB domains are evolutionarily conserved protein domains (14) that participate in protein-protein interactions (15, 16). In the present study, we performed an unbiased proteomic screen and discovered that Neto2 interacts with KCC2. We elucidated the role of this association and characterized its importance in the normal neurophysiological function of KCC2. Because Neto proteins were previously identified as auxiliary subunits of ionotropic glutamate receptors, including kainate and NMDA receptors (17-21), this study further extends the role of the Neto proteins to inhibitory synapses. ResultsNeto2 and KCC2 Interact in Vivo. Recent reports have demonstrated that Neto2 and its homologous protein Neto1 have important functions at excitatory synapses. Neto1 interacts with both the N-methyl D-aspartate receptor (NMDAR) and kainate receptor comp...

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Section: Resultsmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Neto2 is a KCC2 interacting protein required for neuronal Cl ⁻ regulation in hippocampal neurons

Ivakine

Acton

Mahadevan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Cells were dissociated and plated at a density of 50 000 cells/cm 2 on poly-D-lysinecoated AE 12mm round glass coverslips in 24-well plates in glial cell-conditioned B27-supplemented Neurobasal medium (Life Technologies, Carlsbad, CA, USA). The cells were transfected on day 10 in vitro (DIV10) by using calcium phosphate method (Li et al, 2007). The medium was changed to pre-warmed Neurobasal (no supplements) containing 10 mM MgCl2 (transfection medium) 1 h before transfection.…”

Section: Cell Culture Dna Constructs and Transfectionmentioning

confidence: 99%

Molecular mechanisms controlling synaptic recruitment of GluA4 subunit-containing AMPA-receptors critical for functional maturation of CA1 glutamatergic synapses

et al. 2017

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Synaptic recruitment of AMPA receptors (AMPARs) represents a key postsynaptic mechanism driving functional development and maturation of glutamatergic synapses. At immature hippocampal synapses, PKA-driven synaptic insertion of GluA4 is the predominant mechanism for synaptic reinforcement. However, the physiological significance and molecular determinants of this developmentally restricted form of plasticity are not known. Here we show that PKA activation leads to insertion of GluA4 to synaptic sites with initially weak or silent AMPAR-mediated transmission. This effect depends on a novel mechanism involving the extreme C-terminal end of GluA4, which interacts with the membrane proximal region of the C-terminal domain to control GluA4 trafficking. In the absence of GluA4, strengthening of AMPAR-mediated transmission during postnatal development was significantly delayed. These data suggest that the GluA4-mediated activation of silent synapses is a critical mechanism facilitating the functional maturation of glutamatergic circuitry during the critical period of experience-dependent fine-tuning.

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“…In fact, we know that KCC2 plays a structural role in dendritic spine formation during development (Li et al . 2007; Llano et al . 2015), and in mature excitatory synapses KCC2 restricts AMPAR (AMPA‐type glutamate receptor) lateral diffusion in dendritic spines (Gauvain et al .…”

Section: Gpcr Modulation: a Brief Overviewmentioning

confidence: 99%

Regulation of neuronal chloride homeostasis by neuromodulators

Mahadevan

Woodin

2016

The Journal of Physiology

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KCC2 is the central regulator of neuronal Cl− homeostasis, and is critical for enabling strong hyperpolarizing synaptic inhibition in the mature brain. KCC2 hypofunction results in decreased inhibition and increased network hyperexcitability that underlies numerous disease states including epilepsy, neuropathic pain and neuropsychiatric disorders. The current holy grail of KCC2 biology is to identify how we can rescue KCC2 hypofunction in order to restore physiological levels of synaptic inhibition and neuronal network activity. It is becoming increasingly clear that diverse cellular signals regulate KCC2 surface expression and function including neurotransmitters and neuromodulators. In the present review we explore the existing evidence that G‐protein‐coupled receptor (GPCR) signalling can regulate KCC2 activity in numerous regions of the nervous system including the hypothalamus, hippocampus and spinal cord. We present key evidence from the literature suggesting that GPCR signalling is a conserved mechanism for regulating chloride homeostasis. This evidence includes: (1) the activation of group 1 metabotropic glutamate receptors and metabotropic Zn2+ receptors strengthens GABAergic inhibition in CA3 pyramidal neurons through a regulation of KCC2; (2) activation of the 5‐hydroxytryptamine type 2A serotonin receptors upregulates KCC2 cell surface expression and function, restores endogenous inhibition in motoneurons, and reduces spasticity in rats; and (3) activation of A3A‐type adenosine receptors rescues KCC2 dysfunction and reverses allodynia in a model of neuropathic pain. We propose that GPCR‐signals are novel endogenous Cl− extrusion enhancers that may regulate KCC2 function.

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KCC2 Interacts with the Dendritic Cytoskeleton to Promote Spine Development

Cited by 264 publications

References 58 publications

Neto2 is a KCC2 interacting protein required for neuronal Cl ⁻ regulation in hippocampal neurons

Neto2 is a KCC2 interacting protein required for neuronal Cl ⁻ regulation in hippocampal neurons

Molecular mechanisms controlling synaptic recruitment of GluA4 subunit-containing AMPA-receptors critical for functional maturation of CA1 glutamatergic synapses

Regulation of neuronal chloride homeostasis by neuromodulators

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KCC2 Interacts with the Dendritic Cytoskeleton to Promote Spine Development

Cited by 264 publications

References 58 publications

Neto2 is a KCC2 interacting protein required for neuronal Cl − regulation in hippocampal neurons

Neto2 is a KCC2 interacting protein required for neuronal Cl − regulation in hippocampal neurons

Molecular mechanisms controlling synaptic recruitment of GluA4 subunit-containing AMPA-receptors critical for functional maturation of CA1 glutamatergic synapses

Regulation of neuronal chloride homeostasis by neuromodulators

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Neto2 is a KCC2 interacting protein required for neuronal Cl ⁻ regulation in hippocampal neurons

Neto2 is a KCC2 interacting protein required for neuronal Cl ⁻ regulation in hippocampal neurons