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The neural cell adhesion molecule regulates cell-surface delivery of G-protein-activated inwardly rectifying potassium channels via lipid rafts.

Markus Delling, Erhard Wischmeyer, Alexander Dityatev, Vladimir Sytnyk, Rudiger W Veh, Andreas Karschin, Melitta Schachner

J. Neurosci., 2002 Aug 15 , 22, 7154-64

Mice deficient in the neural cell adhesion molecule (NCAM) exhibit increased anxiety and anxiolytic sensitivity to serotonin 5-HT1A receptor agonists. Here, we investigate the relationship between NCAM and 5-HT1A receptor signaling pathways modulating G-protein-activated inwardly rectifying K+ (Kir3) channels. When studying this relationship in cultured hippocampal neurons, we observed that in cells from NCAM-deficient mice, inwardly rectifying K+ (Kir3) currents were increased compared with wild-type controls. Analysis of this modulatory mechanism in Xenopus oocytes and Chinese hamster ovary (CHO) cells revealed that the recombinantly expressed major transmembrane isoforms NCAM140 and NCAM180 specifically reduced inward currents generated by neuronal Kir3.1/3.2 and Kir3.1/3.3 but not by cardiac Kir3.1/3.4 channels. Using fluorescence measurements and surface biotinylation assays, we show that this effect was caused by a reduced surface localization of Kir3 channels. Furthermore, expression of flag-tagged Kir3 channels in cultured neurons of NCAM-deficient mice resulted in a higher transport of these channels into neurites and a higher cell-surface localization compared with wild-type neurons. Neuronal Kir3 channels and NCAM isoforms are associated with cholesterol-rich microdomains (lipid rafts) in CHO cells and in isolated brain membranes. Mutational and pharmacological disruption of the lipid raft association of NCAM140 normalizes surface delivery of channels. We conclude that the transmembrane isoforms of NCAM reduce the transport of Kir3 channels to the cell surface via lipid rafts. Thus, regulation of Kir3 channel activity by NCAM may represent a novel mechanism controlling long-term excitability of neurons.