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

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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References

  1. Catterall, W. A. Cellular and molecular biology of voltage-gated sodium channels. Physiol. Rev. 72, S15–S48 (1992).

    Article  CAS  Google Scholar 

  2. Isom, L. L., Catterall, W. A. Na+ channel subunits and Ig domains. Nature 383, 307 –308 (1996).

    Article  CAS  Google Scholar 

  3. Isom, L. L. et al. Structure and function of the β2 subunit of brain sodium channels, a transmembrane glycoprotein with a CAM-motif. Cell 83, 433–442 (1995).

    Article  CAS  Google Scholar 

  4. Cantrell, A. R., Ma, J. Y., Scheuer, T., Catterall, W. A. Muscarinic modulation of sodium current by activation of protein kinase C in rat hippocampal neurons. Neuron 16, 1019–1025 ( 1996).

    Article  CAS  Google Scholar 

  5. Cantrell, A. R., Scheuer, T., Catterall, W. A. Dopaminergic modulation of sodium current in hippocampal neurons via cAMP-dependent phosphorylation of specific sites in the sodium channel α subunit. J. Neurosci. 17, 7330–7338 (1997).

    Article  CAS  Google Scholar 

  6. Hilborn, M. D., Vaillancourt, R. R., Rane, S. G. Growth factor receptor tyrosine kinases acutely regulate neuronal sodium channels through the src signaling pathway. J. Neurosci. 18, 590–600 ( 1998).

    Article  CAS  Google Scholar 

  7. Fischer, E. H., Charbonneau, H., Tonks, N. K. Protein tyrosine phosphatases: A diverse family of intracellular and transmembrane enzymes. Science 253, 401–406 (1991).

    Article  CAS  Google Scholar 

  8. Barnes, G. et al. Receptor tyrosine phosphatase beta is expressed in the form of proteoglycan and binds to the extracellular matrix protein tenascin. J. Biol. Chem. 269, 14349–14352 (1994).

    Google Scholar 

  9. Levy, J. B. et al. The cloning of a receptor-type protein tyrosine phosphatase expressed in the central nervous system. J. Biol. Chem. 268, 10573–10581 (1993).

    CAS  PubMed  Google Scholar 

  10. Maurel, P, Rauch, U., Flad, M., Margolis, R. K., Margolis, R. U. Phosphacan, a chondroitin sulfate proteoglycan of brain that interacts with neurons and neural cell-adhesion molecules, is an extracellular variant of receptor-type protein tyrosine phosphatase. Proc. Natl. Acad. Sci. USA 91, 2512– 2516 (1994).

    Article  CAS  Google Scholar 

  11. Peles, E. et al. The carbonic anhydrase domain of receptor tyrosine phosphatase beta is a functional ligand for the axonal cell recognition molecule contactin . Cell 82, 251–260 (1995).

    Article  CAS  Google Scholar 

  12. Sakurai, T. et al. Induction of neurite outgrowth through contactin and Nr-CAM by extracellular regions of glial receptor tyrosine phosphatase beta. J. Cell Biol. 136, 907–918 (1997).

    Article  CAS  Google Scholar 

  13. den Hertog, J. et al. Receptor protein tyrosine phosphatase alpha activates pp60c-src and is involved in neuronal differentiation. EMBO J. 12, 3789–3798 (1993).

    Article  CAS  Google Scholar 

  14. Kokel, M., Borland, C. Z., DeLong, L., Horvitz, H. R., Stern, M. J. clr-1 encodes a receptor tyrosine phosphatase that negatively regulates an FGF receptor signaling pathway in Caenorhabditis elegans. Genes Dev. 12, 1425–1437 (1998).

    Article  CAS  Google Scholar 

  15. Meyer-Puttlitz, B. et al. Chondroitin sulfate and chondroitin/keratan sulfate proteoglycans of nervous tissue: developmental changes of neurocan and phosphacan. J. Neurochem. 65, 2327–2337 (1995).

    Article  CAS  Google Scholar 

  16. Canoll, P. D., Petanceska, S., Schlessinger, J., Musacchio, J. M. Three forms of RPTP-β are differentially expressed during gliogenesis in the developing rat brain and during glial cell differentiation in culture . J. Neurosci. Res. 44, 199– 215 (1996).

    Article  CAS  Google Scholar 

  17. Nishiwaki, T., Maeda, N. & Noda, M. Characterization and developmental regulation of proteoglycan-type protein tyrosine phosphatase Z/RPTPβ isoforms. J. Biochem. 123, 458–467 (1998).

    Article  CAS  Google Scholar 

  18. Kim, J. S., Raines, R. T. Ribonuclease S-peptide as a carrier in fusion proteins. Protein Sci. 2, 348– 356 (1993).

    Article  CAS  Google Scholar 

  19. Srinivasan, J., Schachner, M., Catterall, W. A. Interaction of voltage-gated sodium channels with the extracellular matrix molecules tenascin-C and tenascin-R. Proc. Natl. Acad. Sci. USA 95, 15753– 15757 (1998).

    Article  CAS  Google Scholar 

  20. Tsai, W., Morielli, A. D., Cachero, T. G., Peralta, E. G. Receptor protein tyrosine phosphatase alpha participates in the m1 muscarinic acetylcholine receptor-dependent regulation of Kv1. 2 channel activity. EMBO J. 18, 109–118 ( 1999).

    Article  CAS  Google Scholar 

  21. Bliska, J. B., Clemens, J. C., Dixon, J. E., Falkow, S. The Yersinia tyrosine phosphatase: specificity of a bacterial virulence determinant for phosphoproteins in the J774A. 1 macrophage. J. Exp. Med. 176, 1625–1630 (1992).

    Article  CAS  Google Scholar 

  22. Sobko, A., Peretz, A. & Attali, B. Constitutive activation of delayed-rectifier potassium channels by a src family tyrosine kinase in Schwann cells. EMBO J. 17, 4723–4734 ( 1998).

    Article  CAS  Google Scholar 

  23. Holmes, T. C., Fadool, D. A., Ren, R., Levitan, I. B. Association of Src tyrosine kinase with a human potassium channel mediated by SH3 domain. Science 274, 2089–2091 ( 1996).

    Article  CAS  Google Scholar 

  24. Wischmeyer, E., Döring, F., Karschin, A. Acute suppression of inwardly rectifying Kir2. 1 channels by direct tyrosine kinase phosphorylation. J. Biol. Chem. 273, 34063–34068 (1998).

    Article  CAS  Google Scholar 

  25. Yu, X.-M., Askalan, R., Keil, I. G. J., Salter, M. W. NMDA channel regulation by channel-associated protein tyrosine kinase Src. Science 275, 674–678 ( 1997).

    Article  CAS  Google Scholar 

  26. Hu, X.-Q., Singh, N., Mukhopadhyay, D., Akbarali, H. I. Modulation of voltage-dependent Ca2+ channels in rabbit colonic smooth muscle cells by c-Src and focal adhesion kinase. J. Biol. Chem. 273, 5337–5342 ( 1998).

    Article  CAS  Google Scholar 

  27. Snyder, S. E., Li, J., Schauwecker, P. E., McNeill, T. H., Salton, S. R. Comparison of RPTP zeta/beta, phosphacan, and trkB mRNA expression in the developing and adult rat nervous system and induction of RPTP zeta/beta and phosphacan mRNA following brain injury. Mol. Brain Res. 40, 79– 96 (1996).

    Article  CAS  Google Scholar 

  28. Weber, P. et al. Mice deficient for tenascin-R display alterations of the extracellular matrix and decreased axonal conduction velocities in the CNS. J. Neurosci. 19, 4245–4262 (1999).

    Article  CAS  Google Scholar 

  29. Xiao, Z. -C. et al. Tenascin-R is a functional modulator of sodium channel β subunits. J. Biol. Chem. 274, 26511– 26517 (1999).

    Article  CAS  Google Scholar 

  30. Cantrell, A. R., Tibbs, V. C., Westenbroek, R. E., Scheuer, T. & Catterall, W. A. Dopaminergic modulation of voltage-gated Na+ current in rat hippocampal neurons requires anchoring of cAMP-dependent protein kinase. J. Neurosci. 19, RC21 (1999).

    Article  CAS  Google Scholar 

  31. Westenbroek, R. E., Merrick, D. K. & Catterall, W. A. Differential subcellular localization of the R I and RII Na+ channel subtypes in central neurons. Neuron 3, 695– 704 (1989).

    Article  CAS  Google Scholar 

  32. Gordon, D., Merrick, D., Wollner, D. A. & Catterall, W. A. Biochemical properties of sodium channels in a wide range of excitable tissues studied with site-directed antibodies. Biochemistry 27, 7032–7038 (1988).

    Article  CAS  Google Scholar 

  33. Maurel, P., Meyer-Pullitz, B., Glad, M., Margolis, R. U. & Margolis, R. K. Nucleotide sequence and molecular variants of rat receptor-type protein tyrosine phosphatase zeta/beta. DNA Seq. 5, 323–328 ( 1995).

    Article  CAS  Google Scholar 

  34. Auld, V. J. et al. A neutral amino acid change in segment IIS4 dramatically alters the gating properties of the voltage-dependent sodium channel. Proc. Natl. Acad. Sci. USA 87, 323– 327 (1990).

    Article  CAS  Google Scholar 

  35. McCormick, K. A., Srinivasan, J., White, K., Scheuer, T. & Catterall, W. A. The extracellular domain of the β1 subunit is both necessary and sufficient for β1-like modulation of sodium channel gating. J. Biol. Chem. 274, 32638–32646 (1999).

    Article  CAS  Google Scholar 

  36. Evans, G. A., Garcia, G. G., Erwin, R., Howard, O. M. & Farrar, W. L. Pervanadate simulates the effects of interleukin-2 (IL-2) in human T cells and provides evidence for the activation of two distinct tyrosine kinase pathways by IL-2. J. Biol. Chem. 269 , 23407–23412 (1994).

    CAS  PubMed  Google Scholar 

  37. Hartshorne, R. P. & Catterall, W. A. The sodium channel from rat brain. Purification and subunit composition. J. Biol. Chem. 259, 1667–1675 (1984).

    CAS  PubMed  Google Scholar 

  38. Qu, Y., Rogers, J., Tanada, T., Scheuer, T. & Catterall, W. A. Modulation of cardiac Na+ channels expressed in a mammalian cell line and in ventricular myocytes by protein kinase C. Proc. Natl. Acad. Sci. USA 91, 3289–3293 (1994).

    Article  CAS  Google Scholar 

  39. Jurman, M. E., Boland, L. M., Liu, Y. & Yellen, G. Visual identification of individual transfected cells for electrophysiology using antibody-coated beads. Biotechniques 17, 876– 881 (1994).

    CAS  PubMed  Google Scholar 

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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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Ratcliffe, C., Qu, Y., McCormick, K. et al. A sodium channel signaling complex: modulation by associated receptor protein tyrosine phosphatase β. Nat Neurosci 3, 437–444 (2000). https://doi.org/10.1038/74805

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