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:10.1083/jcb.201411008

Cited by 78 publications

(57 citation statements)

References 62 publications

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“…This effect was proposed to be mediated by KCC2’s ability to reduce membrane potential upon activation of GABA A receptors, thereby decreasing the activity of voltage sensitive calcium channels (VSCCs) and overall Ca 2+ dynamics in the cell (Bortone and Polleux, 2009). KCC2 has also been shown to interact with the actin cytoskeleton to regulate spine formation, an activity that appears to be independent from its chloride transport function (Li et al, 2007; Llano et al, 2015). Further work will be required to determine whether KCC2 regulates tangential to radial switch and laminar dispersion of cortical GABAergic interneurons through its effects on GABA signaling, the cytoskeleton or some other mechanism.…”

Section: Discussionmentioning

confidence: 99%

Thalamo-cortical axons regulate the radial dispersion of neocortical GABAergic interneurons

Zechel

Nakagawa

Ibáñez

2016

eLife

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Neocortical GABAergic interneuron migration and thalamo-cortical axon (TCA) pathfinding follow similar trajectories and timing, suggesting they may be interdependent. The mechanisms that regulate the radial dispersion of neocortical interneurons are incompletely understood. Here we report that disruption of TCA innervation, or TCA-derived glutamate, affected the laminar distribution of GABAergic interneurons in mouse neocortex, resulting in abnormal accumulation in deep layers of interneurons that failed to switch from tangential to radial orientation. Expression of the KCC2 cotransporter was elevated in interneurons of denervated cortex, and KCC2 deletion restored normal interneuron lamination in the absence of TCAs. Disruption of interneuron NMDA receptors or pharmacological inhibition of calpain also led to increased KCC2 expression and defective radial dispersion of interneurons. Thus, although TCAs are not required to guide the tangential migration of GABAergic interneurons, they provide crucial signals that restrict interneuron KCC2 levels, allowing coordinated neocortical invasion of TCAs and interneurons.DOI: http://dx.doi.org/10.7554/eLife.20770.001

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Section: Discussionmentioning

confidence: 99%

Thalamo-cortical axons regulate the radial dispersion of neocortical GABAergic interneurons

Zechel

Nakagawa

Ibáñez

2016

eLife

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“…βPix-b has higher GEF activity than βPix-a In addition to the differences in spine localization between βPix-a and -b, their differential GEF activity for Rac1 may contribute to the distinct phenotypes of βPix-a and -b in spine formation. Llano et al (2015) showed that βPix-b-induced Rac1 activation is drastically inhibited in neurons expressing βPix-b construct devoid of DH domain (βPix-bDHm), indicating that the DH domain of βPix-b has GEF activity for Rac1. Here, we tested whether there is a difference in GEF activity between βPix-a and -b.…”

Section: βPix-b Enhances Spine Development and Synapse Formation Thromentioning

confidence: 99%

Src-mediated phosphorylation of βPix-b regulates dendritic spine morphogenesis

Shin

Song

Shin

et al. 2019

Journal of Cell Science

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PAK-interacting guanine nucleotide exchange factor (βPix; also known as Arhgef7) has been implicated in many actin-based cellular processes, including spine morphogenesis in neurons. However, the molecular mechanisms by which βPix controls spine morphology remain elusive. Previously, we have reported the expression of several alternative spliced βPix isoforms in the brain. Here, we report a novel finding that the b isoform of βPix (βPix-b) mediates the regulation of spine and synapse formation. We found that βPix-b, which is mainly expressed in neurons, enhances spine and synapse formation through preferential localization at spines. In neurons, glutamate treatment efficiently stimulates Rac1 GEF activity of βPix-b. The glutamate stimulation also promotes Src-mediated phosphorylation of βPix-b in both an AMPA receptor-and NMDA receptor-dependent manner. Tyrosine 598 (Y598) of βPix-b is identified as the major Src-mediated phosphorylation site. Finally, Y598 phosphorylation of βPix-b enhances its Rac1 GEF activity that is critical for spine and synapse formation. In conclusion, we provide a novel mechanism by which βPix-b regulates activity-dependent spinogenesis and synaptogenesis via Src-mediated phosphorylation.

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“…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 . 2011).…”

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

Abstract: In neurons, KCC2 controls glutamatergic synaptogenesis and regulates actin polymerization in dendritic spines by binding β-PIXb and attenuating its GEF activity toward small GTPase Rac1.

Cited by 78 publications

References 62 publications

Thalamo-cortical axons regulate the radial dispersion of neocortical GABAergic interneurons

Thalamo-cortical axons regulate the radial dispersion of neocortical GABAergic interneurons

Src-mediated phosphorylation of βPix-b regulates dendritic spine morphogenesis

Regulation of neuronal chloride homeostasis by neuromodulators

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