The Journal of General Physiology
Cell MicroControls
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Published online November 12, 2007
doi:10.1085/jgp.200709859
The Journal of General Physiology, Vol. 130, No. 6, 631-645
The Rockefeller University Press, 0022-1295 $30.00
© 2007 Ionescu et al.
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ARTICLE

 Mode Switching Is the Major Mechanism of Ligand Regulation of InsP3 Receptor Calcium Release Channels



Lucian Ionescu1, Carl White1, King-Ho Cheung1, Jianwei Shuai3, Ian Parker3, John E. Pearson4, J. Kevin Foskett1,2, and Don-On Daniel Mak1

1 Department of Physiology and 2 Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
3 Department of Neurobiology and Behavior, University of California, Irvine, CA 92697
4 Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM 87545

Correspondence to J. Kevin Foskett: foskett{at}mail.med.upenn.edu

The inositol 1,4,5-trisphosphate (InsP3) receptor (InsP3R) plays a critical role in generation of complex Ca2+ signals in many cell types. In patch clamp recordings of isolated nuclei from insect Sf9 cells, InsP3R channels were consistently detected with regulation by cytoplasmic InsP3 and free Ca2+ concentrations ([Ca2+]i) very similar to that observed for vertebrate InsP3R. Long channel activity durations of the Sf9-InsP3R have now enabled identification of a novel aspect of InsP3R gating: modal gating. Using a novel algorithm to analyze channel modal gating kinetics, InsP3R gating can be separated into three distinct modes: a low activity mode, a fast kinetic mode, and a burst mode with channel open probability (Po) within each mode of 0.007 ± 0.002, 0.24 ± 0.03, and 0.85 ± 0.02, respectively. Channels reside in each mode for long periods (tens of opening and closing events), and transitions between modes can be discerned with high resolution (within two channel opening and closing events). Remarkably, regulation of channel gating by [Ca2+]i and [InsP3] does not substantially alter channel Po within a mode. Instead, [Ca2+]i and [InsP3] affect overall channel Po primarily by changing the relative probability of the channel being in each mode, especially the high and low Po modes. This novel observation therefore reveals modal switching as the major mechanism of physiological regulation of InsP3R channel activity, with implications for the kinetics of Ca2+ release events in cells.

Abbreviations used in this paper: InsP3, inositol 1,4,5-trisphosphate; InsP3R, InsP3 receptor.


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