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Dual regulation of voltage-gated calcium channels by PtdIns(4,5)P2

Abstract

Voltage-gated calcium channels (VGCCs) conduct calcium into cells after membrane depolarization and are vital for diverse biological events1. They are regulated by various signalling pathways, which has profound functional consequences1,2. The activity of VGCCs decreases with time in whole-cell and inside-out patch-clamp recordings3. This rundown reflects persistent intrinsic modulation of VGCCs in intact cells. Although several mechanisms have been reported to contribute to rundown of L-type channels3,4,5,6, the mechanism of rundown of other types of VGCC is poorly understood. Here we show that phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2), an essential regulator of ion channels and transporters7,8,9,10,11,12,13,14, is crucial for maintaining the activity of P/Q- and N-type channels. Activation of membrane receptors that stimulate hydrolysis of PtdIns(4,5)P2 causes channel inhibition in oocytes and neurons. PtdIns(4,5)P2 also inhibits P/Q-type channels by altering the voltage dependence of channel activation and making the channels more difficult to open. This inhibition is alleviated by phosphorylation by protein kinase A. The dual actions of PtdIns(4,5)P2 and the crosstalk between PtdIns(4,5)P2 and protein kinase A set up a dynamic mechanism through which the activity of VGCCs can be finely tuned by various neurotransmitters, hormones and trophic factors.

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Figure 1: Stabilization of P/Q-type Ca2+ channel activity by PtdIns(4,5)P2 (PIP2).
Figure 2: Voltage-dependent inhibition of P/Q-type Ca2+ channels by PtdIns(4,5)P2 (PIP2).
Figure 3: Crosstalk between phosphorylation by PKA and PtdIns(4,5)P2 (PIP2).
Figure 4: Model of modulation of P/Q-type Ca2+ channels by PtdIns(4,5)P2 and PKA.
Figure 5: Regulation of P/Q- and N-type Ca2+ channels through receptor-mediated hydrolysis of PtdIns(4,5)P2.

References

  1. Hille, B. Ion Channels of Excitable Membranes (Sinauer, Sutherland, 2001)

    Google Scholar 

  2. Catterall, W. A. Structure and regulation of voltage-gated Ca2+ channels. Annu. Rev. Cell Dev. Biol. 16, 521–555 (2000)

    CAS  Article  Google Scholar 

  3. McDonald, T. F., Pelzer, S., Trautwein, W. & Pelzer, D. J. Regulation and modulation of calcium channels in cardiac, skeletal, and smooth muscle cells. Physiol. Rev. 74, 365–507 (1994)

    CAS  Article  Google Scholar 

  4. Chad, J. E. & Eckert, R. An enzymatic mechanism for calcium current inactivation in dialysed Helix neurons. J. Physiol. (Lond.) 378, 31–51 (1986)

    CAS  Article  Google Scholar 

  5. Armstrong, D. & Eckert, R. Voltage-activated calcium channels that must be phosphorylated to respond to membrane depolarization. Proc. Natl Acad. Sci. USA 84, 2518–2522 (1987)

    ADS  CAS  Article  Google Scholar 

  6. Hao, L. Y., Kameyama, A. & Kameyama, M. A cytoplasmic factor, calpastatin and ATP together reverse run-down of Ca2+ channel activity in guinea-pig heart. J. Physiol. (Lond.) 514, 687–699 (1999)

    CAS  Article  Google Scholar 

  7. Hilgemann, D. W. & Ball, R. Regulation of cardiac Na+, Ca2+ exchange and KATP potassium channels by PIP2 . Science 273, 956–959 (1996)

    ADS  CAS  Article  Google Scholar 

  8. Hilgemann, D. W. Cytoplasmic ATP-dependent regulation of ion transporters and channels: mechanisms and messengers. Annu. Rev. Physiol. 59, 193–220 (1997)

    CAS  Article  Google Scholar 

  9. Hilgemann, D. W., Feng, S. & Nasuhoglu, C. The complex and intriguing lives of PIP2 with ion channels and transporters. Science STKE [online] 〈http://stke.sciencemag.org/cgi/content/full/OC_sigtrans;2001/111/re19〉 (2001).

  10. Huang, C-L., Feng, S. & Hilgemann, D. W. Direct activation of inward rectifier potassium channels by PIP2 and its stabilization by Gβγ . Nature 391, 803–806 (1997)

    ADS  Article  Google Scholar 

  11. Womack, K. B. et al. Do phosphatidylinositides modulate vertebrate phototransduction? J. Neurosci. 20, 2792–2799 (2000)

    CAS  Article  Google Scholar 

  12. Kobrinsky, E., Mirshahi, T., Zhang, H., Jin, T. & Logothetis, D. E. Receptor-mediated hydrolysis of plasma membrane messenger PIP2 leads to K+-current desensitization. Nature Cell Biol. 2, 507–514 (2000)

    CAS  Article  Google Scholar 

  13. Chuang, H-h. et al. Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition. Nature 411, 957–962 (2001)

    ADS  CAS  Article  Google Scholar 

  14. Runnels, L. W., Yue, L. & Clapham, D. E. The TRPM7 channel is inactivated by PIP2 hydrolysis. Nature Cell Biol. 4, 329–336 (2002)

    CAS  Article  Google Scholar 

  15. Fukami, K. et al. Antobody to phosphatidylinositol 4,5-bisphosphate inhibits oncogene-induced mitogenesis. Proc. Natl Acad. Sci. USA 85, 9057–9061 (1988)

    ADS  CAS  Article  Google Scholar 

  16. Bean, B. P. Neurotransmitter inhibition of neuronal calcium currents by changes in channel voltage dependence. Nature 340, 153–156 (1989)

    ADS  CAS  Article  Google Scholar 

  17. Liou, H-H., Zhou, S-S. & Huang, C-L. Regulation of ROMK1 channel by protein kinase A via a phosphatidylinositol 4,5-bisphosphate-dependent mechanism. Proc. Natl Acad. Sci. USA 96, 5820–5825 (1999)

    ADS  CAS  Article  Google Scholar 

  18. Bean, B. P. Ion Channels in the Cardiovacular System; Function and Dysfunction (eds Spooner, P. M., Brown, A. M., Catterall, W. A., Kaczorowski, G. J. & Strauss, H. C.) 237–252 (Futura, New York, 1994)

    Google Scholar 

  19. Bean, B. P., Nowycky, M. C. & Tsien, R. W. β-Adrenergic modulation of calcium channels in frog ventricular heart cells. Nature 307, 371–375 (1984)

    ADS  CAS  Article  Google Scholar 

  20. Mori, Y. et al. Primary structure and functional expression from complementary DNA of a brain calcium channel. Nature 350, 398–402 (1991)

    ADS  CAS  Article  Google Scholar 

  21. Stephens, R. et al. Trk receptors use redundant signal transduction pathways involving SHC and PLC-γ1 to mediate NGF responses. Neuron 12, 691–705 (1994)

    CAS  Article  Google Scholar 

  22. Choi, D.-Y., Toledo-Aral, J. J., Segal, R. & Halegoua, S. Sustained signaling by phospholipase C-γ mediates nerve growth factor-triggered gene expression. Mol. Cell. Biol. 21, 2695–2705 (2001)

    CAS  Article  Google Scholar 

  23. Boland, L. M. & Bean, B. P. Modulation of N-type calcium channels in bullfrog sympathetic neurons by luteinizing hormone-releasing hormone: kinetics and voltage dependence. J. Neurosci. 12, 516–533 (1993)

    Article  Google Scholar 

  24. McArdel, C. A., Franklin, J., Green, L. & Hislop, J. N. Signaling, cycling and desensitization of gonadotrophin-releasing hormone receptors. J. Endocrinol. 173, 1–11 (2002)

    Article  Google Scholar 

  25. Rhee, S. G. Regulation of phosphoinositides-specific phospholipase C. Annu. Rev. Biochem. 70, 281–312 (2001)

    CAS  Article  Google Scholar 

  26. McPherson, P. S. et al. A presynaptic inositol-5-phosphatase. Nature 379, 353–357 (1996)

    ADS  CAS  Article  Google Scholar 

  27. Wenk, M. R. et al. PIP kinase Iγ is the major PI(4,5)P2 synthesizing enzyme at the synapse. Neuron 32, 79–88 (2001)

    CAS  Article  Google Scholar 

  28. Cremona, O. & De Camilli, P. Phosphoinositides in membrane traffic at the synapse. J. Cell Sci. 114, 1041–1052 (2001)

    CAS  PubMed  Google Scholar 

  29. Lu, T., Nguyen, B., Zhang, X.-M. & Yang, J. Architecture of a K+ channel inner pore revealed by stoichiometric covalent modification. Neuron 22, 571–580 (1999)

    CAS  Article  Google Scholar 

  30. Yang, J. & Tsien, R. W. Enhancement of N- and L-type calcium channel currents by protein kinase C in frog sympathetic neurons. Neuron 10, 127–136 (1993)

    CAS  Article  Google Scholar 

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Acknowledgements

We thank S. Siegelbaum for comments on the manuscript; Y. Mori for Cav2.1 cDNA; E. Perez-Reyes for β4 cDNA; T. Tanabe for α2δ cDNA; D. J. Julius for p75 and TrkA (wild-type and mutant) cDNAs. This work was supported by a grant to J.Y. from the National Heart, Lung, and Blood Institute. J.Y. is a recipient of the McKnight Scholar Award and the Scholar Research Programme of the EJLB Foundation.

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Correspondence to Jian Yang.

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Wu, L., Bauer, C., Zhen, Xg. et al. Dual regulation of voltage-gated calcium channels by PtdIns(4,5)P2. Nature 419, 947–952 (2002). https://doi.org/10.1038/nature01118

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