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Differential modulation of Cav2.1 channels by calmodulin and Ca2+-binding protein 1

Abstract

Cav2.1 channels, which mediate P/Q-type Ca2+ currents, undergo Ca2+/calmodulin (CaM)-dependent inactivation and facilitation that can significantly alter synaptic efficacy. Here we report that the neuronal Ca2+-binding protein 1 (CaBP1) modulates Cav2.1 channels in a manner that is markedly different from modulation by CaM. CaBP1 enhances inactivation, causes a depolarizing shift in the voltage dependence of activation, and does not support Ca2+-dependent facilitation of Cav2.1 channels. These inhibitory effects of CaBP1 do not require Ca2+, but depend on the CaM-binding domain in the α1 subunit of Cav2.1 channels (α12.1). CaBP1 binds to the CaM-binding domain, co-immunoprecipitates with α12.1 from transfected cells and brain extracts, and colocalizes with α12.1 in discrete microdomains of neurons in the hippocampus and cerebellum. Our results identify an interaction between Ca2+ channels and CaBP1 that may regulate Ca2+-dependent forms of synaptic plasticity by inhibiting Ca2+ influx into neurons.

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Figure 1: CaBP1 binds specifically to the CBD of α12.1.
Figure 2: CaBP1 associates with the α12.1 subunit in tsA-201 cells and rat brain.
Figure 3: CaBP1 colocalizes with α12.1 in rat brain sections.
Figure 4: CaBP1 enhances the inactivation of ICa in tsA-201 cells transfected with Cav2.1 channels.
Figure 5: Fast, Ca2+-independent inactivation of Cav2.1 channels by CaBP1 differs from the modulation of Cav2.1 channels by CaM.
Figure 6: CaBP1 alters the voltage dependence of Cav2.1 activation.
Figure 7: CaBP1 does not support Ca2+-dependent facilitation of Cav2.1 channels.

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References

  1. Miller, R. J. Multiple calcium channels and neuronal function. Science 235, 46–52 (1987).

    Article  CAS  Google Scholar 

  2. Catterall, W. A. Structure and function of neuronal Ca2+ channels and their role in neurotransmitter release. Cell Calcium 24, 307–323 (1998).

    Article  CAS  Google Scholar 

  3. Ikeda, S. R. Voltage-dependent modulation of N-type calcium channels by G-protein βγ subunits. Nature 380, 255–258 (1996).

    Article  CAS  Google Scholar 

  4. Herlitze, S. et al. Modulation of Ca2+ channels by G protein βγ subunits. Nature 380, 258–262 (1996).

    Article  CAS  Google Scholar 

  5. De Waard, M. et al. Direct binding of G-protein βγ complex to voltage-dependent calcium channels. Nature 385, 446–450 (1997).

    Article  CAS  PubMed Central  Google Scholar 

  6. Bezprozvanny, I., Scheller, R. H. & Tsien, R. W. Functional impact of syntaxin on gating of N-type and Q-type calcium channels. Nature 378, 623–626 (1995).

    Article  CAS  Google Scholar 

  7. Zhong, H., Yokoyama, C. T., Scheuer, T. & Catterall, W. A. Reciprocal regulation of P/Q-type Ca2+ channels by SNAP-25, syntaxin and synaptotagmin. Nat. Neurosci. 2, 939–941 (1999).

    Article  CAS  Google Scholar 

  8. Wiser, O., Bennett, M. K. & Atlas, D. Functional interaction of syntaxin and SNAP-25 with voltage-sensitive L- and N-type Ca2+ channels. EMBO J. 15, 4100–4110 (1996).

    Article  CAS  PubMed Central  Google Scholar 

  9. Lee, A. et al. Ca2+/calmodulin binds to and modulates P/Q-type calcium channels. Nature 339, 155–159 (1999).

    Article  Google Scholar 

  10. Lee, A., Scheuer, T. & Catterall, W. A. Ca2+/calmodulin-dependent facilitation and inactivation of P/Q-type Ca2+ channels. J. Neurosci. 20, 6830–6838 (2000).

    Article  CAS  Google Scholar 

  11. Qin, N., Olcese, R., Bransby, M., Lin, T. & Birnbaumer, L. Ca2+-induced inhibition of the cardiac Ca2+ channel depends on calmodulin. Proc. Natl. Acad. Sci. USA 96, 2435–2438 (1999).

    Article  CAS  Google Scholar 

  12. Peterson, B. Z., DeMaria, C. D. & Yue, D. T. Calmodulin is the Ca2+ sensor for Ca2+-dependent inactivation of L-type calcium channels. Neuron 22, 549–558 (1999).

    Article  CAS  PubMed Central  Google Scholar 

  13. Zühlke, R. G., Pitt, G. S., Deisseroth, K., Tsien, R. W. & Reuter, H. Calmodulin supports both inactivation and facilitation of L-type calcium channels. Nature 399, 159–161 (1999).

    Article  Google Scholar 

  14. Pate, P. et al. Determinants for calmodulin binding on voltage-dependent Ca2+ channels. J. Biol. Chem. 275, 39786–39792 (2000).

    Article  CAS  PubMed Central  Google Scholar 

  15. DeMaria, C. D., Soong, T., Alseikhan, B. A., Alvania, R. S. & Yue, D. T. Calmodulin bifurcates the local Ca2+ signal that modulates P/Q-type Ca2+ channels. Nature 411, 484–489 (2001).

    Article  CAS  Google Scholar 

  16. Forsythe, I. D., Tsujimoto, T., Barnes-Davies, M., Cuttle, M. F. & Takahashi, T. Inactivation of presynaptic calcium current contributes to synaptic depression at a fast central synapse. Neuron 20, 797–807 (1998).

    Article  CAS  Google Scholar 

  17. Cuttle, M. F., Tsujimoto, T., Forsythe, I. D. & Takahashi, T. Facilitation of the presynaptic calcium current at an auditory synapse in rat brainstem. J. Physiol. (Lond.) 512, 723–729 (1998).

    Article  CAS  Google Scholar 

  18. Borst, J. G. & Sakmann, B. Facilitation of presynaptic calcium currents in the rat brainstem. J. Physiol. (Lond.) 513, 149–155 (1998).

    Article  CAS  Google Scholar 

  19. Dunlap, K., Luebke, J. I. & Turner, T. J. Exocytotic Ca2+ channels in mammalian central neurons. Trends Neurosci. 18, 89–98 (1995).

    Article  CAS  PubMed Central  Google Scholar 

  20. Wheeler, D. B., Randall, A. & Tsien, R. W. Roles of N-type and Q-type Ca2+ channels in supporting hippocampal synaptic transmission. Science 264, 107–111 (1994).

    Article  CAS  PubMed Central  Google Scholar 

  21. Polans, A., Baehr, W. & Palczewski, K. Turned on by Ca2+! The physiology and pathology of Ca2+-binding proteins in the retina. Trends Neurosci. 19, 547–554 (1996).

    Article  CAS  Google Scholar 

  22. Burgoyne, R. D. & Weiss, J. L. The neuronal calcium sensor family of Ca2+-binding proteins. Biochem. J. 353, 1–12 (2001).

    Article  CAS  PubMed Central  Google Scholar 

  23. Sallese, M. et al. The G-protein-coupled receptor kinase GRK4 mediates homologous desensitization of metabotropic glutamate receptor 1. FASEB J. 14, 2569–2580 (2000).

    Article  CAS  Google Scholar 

  24. Schaad, N. C. et al. Direct modulation of calmodulin targets by the neuronal calcium sensor NCS-1. Proc. Natl. Acad. Sci. USA 93, 9253–9258 (1996).

    Article  CAS  Google Scholar 

  25. Haeseleer, F. et al. Five members of a novel Ca2+-binding protein (CABP) subfamily with similarity to calmodulin. J. Biol. Chem. 275, 1247–1260 (2000).

    Article  CAS  PubMed Central  Google Scholar 

  26. Stea, A. et al. The localization and functional properties of a rat brain α1A calcium channel reflect similarities to neuronal Q- and P-type channels. Proc. Natl. Acad. Sci. USA 91, 10576–10580 (1994).

    Article  CAS  Google Scholar 

  27. Seidenbecher, C. I. et al. Caldendrin, a novel neuronal calcium-binding protein confined to the somato-dendritic compartment. J. Biol. Chem. 273, 21324–21331 (1998).

    Article  CAS  Google Scholar 

  28. Westenbroek, R. E. et al. Immunochemical identification and subcellular distribution of the α1A subunits of brain calcium channels. J. Neurosci. 15, 6403–6418 (1995).

    Article  CAS  Google Scholar 

  29. Chao, S. H., Suzuki, Y., Zysk, J. R. & Cheung, W. Y. Activation of calmodulin by various metal cations as a function of ionic radius. Mol. Pharmacol. 26, 75–82 (1984).

    CAS  PubMed  Google Scholar 

  30. Rodney, G. G., Williams, B. Y., Strasburg, G. M., Beckingham, K. & Hamilton, S. L. Regulation of RYR1 activity by Ca2+ and calmodulin. Biochemistry 39, 7807–7812 (2000).

    Article  CAS  Google Scholar 

  31. Yamaki, T. & Hidaka, H. Ca2+-independent stimulation of cyclic GMP-dependent protein kinase by calmodulin. Biochem. Biophys. Res. Commun. 94, 727–733 (1980).

    Article  CAS  Google Scholar 

  32. Greenlee, D. V., Andreasen, T. J. & Storm, D. R. Calcium-independent stimulation of Bordetella pertussis adenylate cyclase. Biochemistry 21, 2759–2764 (1982).

    Article  CAS  Google Scholar 

  33. Rudnicka-Nawrot, M. et al. Changes in biological activity and folding of guanylate cyclase-activating protein 1 as a function of calcium. Biochemistry 37, 248–257 (1998).

    Article  CAS  Google Scholar 

  34. Haeseleer, F. et al. Molecular characterization of a third member of the guanylyl cyclase-activating protein subfamily. J. Biol. Chem. 274, 6526–6535 (1999).

    Article  CAS  Google Scholar 

  35. McFerran, B. W., Graham, M. E. & Burgoyne, R. D. Neuronal Ca2+ sensor 1, the mammalian homologue of frequenin, is expressed in chromaffin and PC12 cells and regulates neurosecretion from dense-core granules. J. Biol. Chem. 273, 22768–22772 (1998).

    Article  CAS  Google Scholar 

  36. Chen, X. L. et al. Overexpression of rat neuronal calcium sensor-1 in rodent NG108-15 cells enhances synapse formation and transmission. J. Physiol. (Lond.) 532, 649–659 (2001).

    Article  CAS  Google Scholar 

  37. Gomez, M. et al. Ca2+ signaling via the neuronal calcium sensor-1 regulates associative learning and memory in C. elegans. Neuron 30, 241–248 (2001).

    Article  CAS  Google Scholar 

  38. Weiss, J. L., Archer, D. A. & Burgoyne, R. D. Neuronal Ca2+ sensor-1/frequenin functions in an autocrine pathway regulating Ca2+ channels in bovine adrenal chromaffin cells. J. Biol. Chem. 275, 40082–40087 (2000).

    Article  CAS  Google Scholar 

  39. Sakurai, T., Westenbroek, R. E., Rettig, J., Hell, J. & Catterall, W. A. Biochemical properties and subcellular distribution of the BI and rbA isoforms of α1A subunits of brain calcium channels. J. Cell Biol. 134, 511–528 (1996).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by NIH Research Grant R01 NS22625 to W.A.C, a NSRA postdoctoral research fellowship from NIH (F32 NS10645) to A.L., NIH Research Grant R01 EY08061 to K.P. and research grants from Research to Prevent Blindness, Inc., the Alcon Research Institute and the E.K. Bishop Foundation to K.P.

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Correspondence to William A. Catterall.

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Lee, A., Westenbroek, R., Haeseleer, F. et al. Differential modulation of Cav2.1 channels by calmodulin and Ca2+-binding protein 1. Nat Neurosci 5, 210–217 (2002). https://doi.org/10.1038/nn805

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