| First Author | Roussa E | Year | 2016 |
| Journal | J Cell Sci | Volume | 129 |
| Issue | 18 | Pages | 3485-98 |
| PubMed ID | 27505893 | Mgi Jnum | J:246426 |
| Mgi Id | MGI:5924118 | Doi | 10.1242/jcs.189860 |
| Citation | Roussa E, et al. (2016) The membrane trafficking and functionality of the K+-Cl- co-transporter KCC2 is regulated by TGF-beta2. J Cell Sci 129(18):3485-98 |
| abstractText | 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 beta2 (TGF-beta2) as a new regulator of KCC2 membrane trafficking and functional activation. TGF-beta2 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-beta2 to cAMP-response-element-binding protein (CREB) and Ras-associated binding protein 11b (Rab11b) as the underlying mechanism for TGF-beta2-mediated KCC2 trafficking and functional activation. TGF-beta2 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-beta2-dependent KCC2 trafficking, surface expression and functionality. Thus, TGF-beta2 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. |
