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Type III InsP3 receptor channel stays open in the presence of increased calcium

Nature volume 396, pages 81–84 (1998)Cite this article

Abstract

The inositol 1,4,5-trisphosphate receptor (InsP3R) is the main calcium(Ca2+) release channel in most tissues. Three isoforms have been identified1,2,3,4,5,6, but only types I and II InsP3R have been characterized7,8. Here we examine the functional properties of the type III InsP3R because this receptor is restricted to the trigger zone from which Ca2+ waves originate9,10,11 and it has distinctive InsP3-binding properties12,13. We find that type III InsP3R forms Ca2+ channels with single-channel currents that are similar to those of type I InsP3R; however, the open probability of type III InsP3R isoform increases monotonically with increased cytoplasmic Ca2+ concentration, whereas the type I isoform has a bell-shaped dependence on cytoplasmic Ca2+. The properties of type III InsP3R provide positive feedback as Ca2+ is released; the lack of negative feedback allows complete Ca2+ release from intracellular stores. Thus, activation of type III InsP3R in cells that express only this isoform results in a single transient, but global, increase in the concentration of cytosolic Ca2+. The bell-shaped Ca2+-dependence curve of type I InsP3R is ideal for supporting Ca2+ oscillations, whereas the properties of type III InsP3R are better suited to signal initiation.

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Figure 1: RIN-5F cells preferentially express Type III InsP3R.
Figure 2: Type III InsP3R is an InsP3-gated Ca2+ channel.
Figure 3: Single channel open probability for type I and type III InsP3R as a function of Ca2+ concentration.
Figure 4: Ca2+ signalling patterns in RIN-5F cells and rat hepatocytes.
Figure 5: Subcellular Ca2+ release differs between RIN-5F and SKHep1 cells.

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Acknowledgements

We thank E. Kaftan for all his assistance during the execution of these experiments, J. Putney for suggesting RIN-5F cells as source of type III InsP3R, and J. Brown for comments on the manuscript. This work was supported by NIH grants (to B.E.E. and M.H.N.), an Established Investigator Grant from the American Heart Association (to M.H.N.), and by the Yale Liver Center.

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Authors and Affiliations

  1. Department of Physiology, University of Connecticut Health Center, Farmington, 06030, Connecticut, USA

    Robert E. Hagar

  2. Departments of Medicine and Cell Biology, Yale University, New Haven, 06520, Connecticut, USA

    Angela D. Burgstahler & Michael H. Nathanson

  3. Departments of Pharmacology and Cellular and Molecular Physiology, Yale University, New Haven, 06520, Connecticut, USA

    Barbara E. Ehrlich

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  1. Robert E. Hagar
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Correspondence to Robert E. Hagar.

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Hagar, R., Burgstahler, A., Nathanson, M. et al. Type III InsP3 receptor channel stays open in the presence of increased calcium. Nature 396, 81–84 (1998). https://doi.org/10.1038/23954

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