A sodium channel signaling complex: modulation by associated receptor protein tyrosine phosphatase β

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Abstract

Voltage-gated sodium channels in brain neurons were found to associate with receptor protein tyrosine phosphatase β (RPTPβ) and its catalytically inactive, secreted isoform phosphacan, and this interaction was regulated during development. Both the extracellular domain and the intracellular catalytic domain of RPTPβ interacted with sodium channels. Sodium channels were tyrosine phosphorylated and were modulated by the associated catalytic domains of RPTPβ. Dephosphorylation slowed sodium channel inactivation, positively shifted its voltage dependence, and increased whole-cell sodium current. Our results define a sodium channel signaling complex containing RPTPβ, which acts to regulate sodium channel modulation by tyrosine phosphorylation.

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Figure 1: Co-immunoprecipitation of RPTPβ with sodium channels in P1 and P16 rat brain membrane lysates.
Figure 2: Interaction of sodium channels with the extracellular carbonic anhydrase domain of RPTPβ.
Figure 3: Co-immunoprecipitation of transfected sodium channel subunits with an endogenously expressed RPTPβ isoform in tsA-201 cells.
Figure 4: Interaction of β1/β2 chimeras with RPTPβ in tsA-201 cells.
Figure 5: Sodium channel α subunits are tyrosine phosphorylated, and sodium channel α and β1 subunits co-immunoprecipitate with wild-type and mutant RPTPβ cytoplasmic domain proteins.
Figure 6: Sodium channel α subunits are modulated after associating with RPTPβ phosphatase domains.
Figure 7: Effects of sodium pervanadate on PTPwt-cotransfected cells.

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Acknowledgements

We thank Carl Baker for technical assistance. CFR was supported by a fellowship from the Wellcome Trust. This research was supported by NIH Research Grants NS25704 (W.A.C.) and GM18848 (J.E.D.).

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Correspondence to William A. Catterall.

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