Rapid ligand‐regulated gating kinetics of single inositol 1,4,5‐trisphosphate receptor Ca 2+ release channels

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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.