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

Nature volume 419, pages 947–952 (2002)Cite this article

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](/articles/nature01118#ref-CR9 "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](/articles/nature01118#ref-CR10 "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)"),[11](/articles/nature01118#ref-CR11 "Womack, K. B. et al. Do phosphatidylinositides modulate vertebrate phototransduction? J. Neurosci. 20, 2792–2799 (2000)"),[12](/articles/nature01118#ref-CR12 "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)"),[13](/articles/nature01118#ref-CR13 "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)"),[14](/articles/nature01118#ref-CR14 "Runnels, L. W., Yue, L. & Clapham, D. E. The TRPM7 channel is inactivated by PIP2 hydrolysis. Nature Cell Biol. 4, 329–336 (2002)"), 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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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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  1. Li Wu and Claudia S. Bauer: These authors contributed equally to this work
  2. Jian Yang: Correspondence and requests for materials should be addressed to J.Y.

Authors and Affiliations

  1. Department of Biological Sciences, Columbia University, New York, New York, 10027, USA
    Li Wu, Claudia S. Bauer, Xiao-guang Zhen, Cheng Xie & Jian Yang

Authors

  1. Li Wu
  2. Claudia S. Bauer
  3. Xiao-guang Zhen
  4. Cheng Xie
  5. Jian Yang

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Correspondence toJian 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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