The membrane trafficking and functionality of the K+-Cl- co-transporter KCC2 is regulated by TGF-β2.

Autor:	Roussa E; Institute of Anatomy and Cell Biology, Department of Molecular Embryology, Faculty of Medicine, University of Freiburg, Albertstrasse 17, Freiburg D-79104, Germany Institute of Anatomy and Cell Biology, Department of Neuroanatomy, Faculty of Medicine, University of Freiburg, Albertstrasse 17, Freiburg D-79104, Germany kerstin.krieglstein@anat.uni-freiburg.de eleni.roussa@anat.uni-freiburg.de., Speer JM; Institute of Anatomy and Cell Biology, Department of Molecular Embryology, Faculty of Medicine, University of Freiburg, Albertstrasse 17, Freiburg D-79104, Germany., Chudotvorova I; Institute of Anatomy and Cell Biology, Department of Molecular Embryology, Faculty of Medicine, University of Freiburg, Albertstrasse 17, Freiburg D-79104, Germany., Khakipoor S; Institute of Anatomy and Cell Biology, Department of Molecular Embryology, Faculty of Medicine, University of Freiburg, Albertstrasse 17, Freiburg D-79104, Germany., Smirnov S; Institute of Biotechnology, University of Helsinki, Viikinkaari 9, Helsinki FIN-00014, Finland., Rivera C; Institute of Biotechnology, University of Helsinki, Viikinkaari 9, Helsinki FIN-00014, Finland., Krieglstein K; Institute of Anatomy and Cell Biology, Department of Molecular Embryology, Faculty of Medicine, University of Freiburg, Albertstrasse 17, Freiburg D-79104, Germany kerstin.krieglstein@anat.uni-freiburg.de eleni.roussa@anat.uni-freiburg.de.
Jazyk:	angličtina
Zdroj:	Journal of cell science [J Cell Sci] 2016 Sep 15; Vol. 129 (18), pp. 3485-98. Date of Electronic Publication: 2016 Aug 05.
DOI:	10.1242/jcs.189860
Abstrakt:	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 β2 (TGF-β2) as a new regulator of KCC2 membrane trafficking and functional activation. TGF-β2 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-β2 to cAMP-response-element-binding protein (CREB) and Ras-associated binding protein 11b (Rab11b) as the underlying mechanism for TGF-β2-mediated KCC2 trafficking and functional activation. TGF-β2 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-β2-dependent KCC2 trafficking, surface expression and functionality. Thus, TGF-β2 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. Competing Interests: The authors declare no competing or financial interests. (© 2016. Published by The Company of Biologists Ltd.)
Databáze:	MEDLINE
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