Clustering of InsP3 receptors by InsP3 retunes their regulation by InsP3 and Ca2+ (original) (raw)

Nature volume 458, pages 655–659 (2009)Cite this article

Abstract

The versatility of Ca2+ signals derives from their spatio-temporal organization1,2. For Ca2+ signals initiated by inositol-1,4,5-trisphosphate (InsP3), this requires local interactions between InsP3 receptors (InsP3Rs)3,4 mediated by their rapid stimulation and slower inhibition4 by cytosolic Ca2+. This allows hierarchical recruitment of Ca2+ release events as the InsP3 concentration increases5. Single InsP3Rs respond first, then clustered InsP3Rs open together giving a local ‘Ca2+ puff’, and as puffs become more frequent they ignite regenerative Ca2+ waves1,5,6,7,8,9. Using nuclear patch-clamp recording10, here we demonstrate that InsP3Rs are initially randomly distributed with an estimated separation of ∼1 μm. Low concentrations of InsP3 cause InsP3Rs to aggregate rapidly and reversibly into small clusters of about four closely associated InsP3Rs. At resting cytosolic [Ca2+], clustered InsP3Rs open independently, but with lower open probability, shorter open time, and less InsP3 sensitivity than lone InsP3Rs. Increasing cytosolic [Ca2+] reverses the inhibition caused by clustering, InsP3R gating becomes coupled, and the duration of multiple openings is prolonged. Clustering both exposes InsP3Rs to local Ca2+ rises and increases the effects of Ca2+. Dynamic regulation of clustering by InsP3 retunes InsP3R sensitivity to InsP3 and Ca2+, facilitating hierarchical recruitment of the elementary events that underlie all InsP3-evoked Ca2+ signals3,5.

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Acknowledgements

This work was supported by The Wellcome Trust (C.W.T.), The Biotechnology and Biological Sciences Research Council (C.W.T.), a scholarship from the Jameel Family Trust (T.-U.-R.), and the IRTG ‘Genomics and Systems Biology of Molecular Networks’ of the Deutsche Forschungsgemeinschaft (A.S.). We thank S. Dedos for help with DT40 cells, D. Prole and B. Billups for advice, and T. Kurosaki for providing DT40-KO cells.

Author Contributions T.-U.-R. performed all experiments and, with C.W.T., analysed the data. A.S. and M.F. performed the modelling and contributed to discussions of diffusion. C.W.T. and T.-U.-R. wrote the paper with input from A.S. and M.F. The project was directed by C.W.T.

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Authors and Affiliations

  1. Department of Pharmacology, Tennis Court Road, Cambridge CB2 1PD, UK,
    Taufiq-Ur-Rahman & Colin W. Taylor
  2. Mathematical Cell Physiology, Max Delbrück Centre for Molecular Medicine, Robert Rössle Str. 10, 13092 Berlin, Germany ,
    Alexander Skupin & Martin Falcke
  3. Helmholtz Centre Berlin for Materials and Energy, Glienicker Str. 100, 14109 Berlin, Germany ,
    Martin Falcke

Authors

  1. Taufiq-Ur-Rahman
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  2. Alexander Skupin
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  3. Martin Falcke
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  4. Colin W. Taylor
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Corresponding author

Correspondence toColin W. Taylor.

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Supplementary Information

This file contain Supplementary Methods and Data, a Supplementary Discussion, Supplementary Parameter Tables 1-2, Supplementary References, Supplementary Tables 1-4 and Supplementary Figures 1-9 with Legends. (PDF 1452 kb)

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Taufiq-Ur-Rahman, Skupin, A., Falcke, M. et al. Clustering of InsP3 receptors by InsP3 retunes their regulation by InsP3 and Ca2+.Nature 458, 655–659 (2009). https://doi.org/10.1038/nature07763

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Editorial Summary

InsP3 receptors and channel opening

Inositol trisphosphate (InsP3) is a second messenger that triggers release of Ca2+ from intracellular stores through its cognate receptor — a ligand-gated ion channel. This paper shows that InsP3 receptors aggregate in response to InsP3, resulting in a lower probability of channel opening, and that increases in intracellular Ca2+ can effectively relieve this inhibition and enhance the coupling between receptors in a cluster. This mechanism may serve to enhance the sensitivity to changes in intracellular Ca2+.

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