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It takes two steps to localize a sodium channel to its proper location at the entrance to the axon, based on results on page 571 from Fache et al. Their findings are consistent with a targeting system involving both tethering and selective elimination., w9 k7 K! ?' d/ O4 c- i
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The boundary between the neuronal cell body and the axon, called the axonal initial segment (AIS), is a dense network of actin and ankyrin G and ? IV spectrin, where clusters of sodium channels initiate action potentials. A cytoplasmic loop from the Nav1.2 sodium channel binds to ankyrin and, when added to non-AIS proteins, can direct them to this segment. The authors now show that this loop contains two separate domains essential for precise localization.
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0 n7 n& y* p9 bOne domain tethers the protein to ankyrin, and the other removes it from surface of the rest of the neuron. Mutation of the first domain—a 27-residue stretch that binds to ankyrin—caused chimeric proteins with the mutant loop to localize throughout the cell.
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A nearby but nonoverlapping domain was also needed to limit protein localization to the AIS by removing proteins from the surface elsewhere. Newly made chimeric proteins were sent to the plasma membrane all around the cell body, including the AIS. Those that did not land at or move to the AIS were then internalized, as were proteins that somehow found their way to the far end of the axon. Removal of 19 residues in the NH2-terminal portion of the loop abolished this endocytosis, and protein accumulated throughout the neuron.
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It is not clear what prevents the endocytosis in the AIS, although linkage to ankyrin does not seem to be necessary. Perhaps endocytosis is generally limited in the AIS. The NH2-terminal portion of the loop is unlike any known internalization sequence and should provide a good starting point to identify proteins needed for this endocytic pathway.(AIS proteins (green) are internalized ev) |
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发表于 2009-3-6 08:17
发表于 2015-5-24 15:17
