The membrane trafficking and functionality of the K+-Cl- co-transporter KCC2 is regulated by TGF-beta 2

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Roussa , E , Speer , J M , Chudotvorova , I , Khakipoor , S , Smirnov , S , Rivera Baeza , C & Krieglstein , K 2016 , ' The membrane trafficking and functionality of the K+-Cl- co-transporter KCC2 is regulated by TGF-beta 2 ' , Journal of Cell Science , vol. 129 , no. 18 , pp. 3485-3498 . https://doi.org/10.1242/jcs.189860

Title: The membrane trafficking and functionality of the K+-Cl- co-transporter KCC2 is regulated by TGF-beta 2
Author: Roussa, Eleni; Speer, Jan Manuel; Chudotvorova, Ilona; Khakipoor, Shokoufeh; Smirnov, Sergei; Rivera Baeza, Claudio; Krieglstein, Kerstin
Contributor: University of Helsinki, Neuroscience Center
University of Helsinki, Neuroscience Center
Date: 2016-09-15
Language: eng
Number of pages: 14
Belongs to series: Journal of Cell Science
ISSN: 0021-9533
URI: http://hdl.handle.net/10138/172348
Abstract: Functional activation of the neuronal K+-Cl- co-transporter KCC2 (also known as SLC12A5) is a prerequisite for shifting GABAA responses from depolarizing to hyperpolarizing during development. Here, we introduce transforming growth factor beta 2 (TGF-beta 2) as a new regulator of KCC2 membrane trafficking and functional activation. TGF-beta 2 controls membrane trafficking, surface expression and activity of KCC2 in developing and mature mouse primary hippocampal neurons, as determined by immunoblotting, immunofluorescence, biotinylation of surface proteins and KCC2-mediated Cl- extrusion. We also identify the signaling pathway from TGF-beta 2 to cAMP-response-element-binding protein (CREB) and Ras-associated binding protein 11b (Rab11b) as the underlying mechanism for TGF-beta 2-mediated KCC2 trafficking and functional activation. TGF-beta 2 increases colocalization and interaction of KCC2 with Rab11b, as determined by 3D stimulated emission depletion (STED) microscopy and co-immunoprecipitation, respectively, induces CREB phosphorylation, and enhances Rab11b gene expression. Loss of function of either CREB1 or Rab11b suppressed TGF-beta 2-dependent KCC2 trafficking, surface expression and functionality. Thus, TGF-beta 2 is a new regulatory factor for KCC2 functional activation and membrane trafficking, and a putative indispensable molecular determinant for the developmental shift of GABAergic transmission.
Subject: KCC2
CREB
Growth factor
Neuronal development
Rab11b
GROWTH-FACTOR-BETA
CATION-CHLORIDE COTRANSPORTERS
DEVELOPMENTAL UP-REGULATION
LONG-TERM CHANGES
NEURONS IN-VITRO
HIPPOCAMPAL-NEURONS
DENDRITIC SPINES
SENSORY NEURONS
DOWN-REGULATION
SALIVARY DUCTS
3112 Neurosciences
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