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EMBO reports 8, 11, 1044–1051 (2007)
doi:10.1038/sj.embor.7401087
AOP Published online: 12 October 2007
Rapid ligand-regulated gating kinetics of single inositol 1,4,5-trisphosphate receptor Ca2+ release channels
Don-On Daniel Mak1, John E Pearson3, King Pan Campion Loong1, Suman Datta1, Marisabel Fernández-Mongil1 & J Kevin Foskett1, 2
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1 Department of Physiology and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
2 Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
3 Department of Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA
To whom correspondence should be addressed
Don-On Daniel Mak Tel: +1 215 898 0468; Fax: +1 215 573 6808; E-mail: dmak@mail.med.upenn.edu
Received 27 April 2007; Accepted 31 August 2007; Published online 12 October 2007.
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Abstract
The ubiquitous inositol 1,4,5-trisphosphate receptor (InsP3R) intracellular Ca2+ release channel is engaged by thousands of plasma membrane receptors to generate Ca2+ signals in all cells. Understanding how complex Ca2+ signals are generated has been hindered by a lack of information on the kinetic responses of the channel to its primary ligands, InsP3 and Ca2+, which activate and inhibit channel gating. Here, we describe the kinetic responses of single InsP3R channels in native endoplasmic reticulum membrane to rapid ligand concentration changes with millisecond resolution, using a new patch-clamp configuration. The kinetics of channel activation and deactivation showed novel Ca2+ regulation and unexpected ligand cooperativity. The kinetics of Ca2+-mediated channel inhibition showed the single-channel bases for fundamental Ca2+ release events and Ca2+ release refractory periods. These results provide new insights into the channel regulatory mechanisms that contribute to complex spatial and temporal features of intracellular Ca2+ signals.
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