PubMed 20610389

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Title: Functional consequences of the interactions between the neural cell adhesion molecule NCAM, the receptor tyrosine kinase TrkB and the inwardly rectifying K+ channel Kir3.3.

Authors: Ralf Kleene, Claas Cassens, Robert Baehring, Thomas Theis, Mei-Fang Xiao, Alexander Dityatev, Claus Schafer-Nielsen, Frank Doering, Erhard Wischmeyer, Melitta Schachner

Journal, date & volume: , 2010 Jul 6 , ,

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Cell adhesion molecules and neurotrophin receptors are crucial for the development and the function of the nervous system. Among downstream effectors of neurotrophin receptors and recognition molecules are ion channels. Here, we provide evidence that G-protein coupled inwardly rectifying K(+) channel Kir3.3 directly binds to the neural cell adhesion molecule NCAM and the neurotrophin receptor TrkB. We identified the binding sites for NCAM and TrkB at the C-terminal intracellular domain of Kir3.3. The interaction between NCAM, TrkB and Kir3.3 was supported by immunocytochemical co-localization of Kir3.3, NCAM, and/or TrkB at the surface of hippocampal neurons. Co-expression of TrkB and Kir3.1/3.3 in Xenopus oocytes increased the K(+) currents evoked by Kir3.1/3.3 channels. This current enhancement was reduced by the concomitant co-expression with NCAM. Both surface fluorescence measurements of microinjected oocytes and cell surface biotinylation of transfected CHO cells indicated that the cell membrane localization of Kir3.3 is regulated by TrkB and NCAM. Furthermore, the level of Kir3.3, but not of Kir3.2, at the plasma membranes is reduced in TrkB-deficient mice, supporting the notion that TrkB regulates the cell surface expression of Kir3.3. The premature expression of developmentally late appearing Kir3.1/3.3 in hippocampal neurons leads to a reduction of NCAM-induced neurite outgrowth. Our observations indicate a decisive role for a neuronal K(+) channel in regulating NCAM-dependent neurite outgrowth and attribute a physiologically meaningful role of the functional interplay of Kir3.3, NCAM and TrkB in ontogeny.