Abstract
G protein–gated potassium (Kir3) channels are important for controlling neuronal excitability in the brain. Using a proteomics approach, we have identified a unique rodent intracellular protein, sorting nexin 27 (SNX27), which regulates the trafficking of Kir3 channels. Like most sorting nexins, SNX27 possesses a functional PX domain that selectively binds the membrane phospholipid phosphatidylinositol-3-phosphate (PI3P) and is important for trafficking to the early endosome. SNX27, however, is the only sorting nexin to contain a PDZ domain. This PDZ domain discriminates between channels with similar class I PDZ-binding motifs, associating with the C-terminal end of Kir3.3 and Kir3.2c (−ESKV), but not with that of Kir2.1 (−ESEI) or Kv1.4 (−ETDV). SNX27 promotes the endosomal movement of Kir3 channels, leading to reduced surface expression, increased degradation and smaller Kir3 potassium currents. The regulation of endosomal trafficking via sorting nexins reveals a previously unknown mechanism for controlling potassium channel surface expression.
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Acknowledgements
We thank C. Vandenberg and D. Leonoudakis for their invaluable advice for the proteomics study, D. Clapham for providing Kir3.3 and Kir3.4 cDNAs, M. Sheng for providing PSD-95 and Chapsyn-110 cDNAs, L. Jan and E. Cooper for providing Kv1.4 cDNA, I. Verma for the use of his confocal microscope, and C. Lüscher, M. Montminy and members of the Slesinger lab for reading versions of the manuscript. This work was made possible by financial support from the McKnight Endowment for Neuroscience (P.A.S.), the Hearst Foundation (P.A.S.) and the National Institute of Neurological Disorders and Stroke (NIH R01 NS37682, P.A.S.).
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M.-L.L., R.N. and P.A.S. were responsible for all cell biological and electrophysiological experiments, data interpretation and writing the manuscript. C.A. and J.T. assisted in preparing mutants and conducting in vitro protein binding assays. M.-L.L., I.M. and J.R.Y. (III) were responsible for conducting, interpreting, and writing-up the HPLC-MS-MS proteomics experiments. M.-L.L., C.M.A. and P.E.S. were responsible for conducting, interpreting, and writing-up the in situ experiments. P.A.S. supervised all of the experiments, including the design, data analysis and interpretation.
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Lunn, ML., Nassirpour, R., Arrabit, C. et al. A unique sorting nexin regulates trafficking of potassium channels via a PDZ domain interaction. Nat Neurosci 10, 1249–1259 (2007). https://doi.org/10.1038/nn1953
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DOI: https://doi.org/10.1038/nn1953
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