Quantal Ca²⁺ release mediated by very few IP₃ receptors that rapidly inactivate allows graded responses to IP₃

Inositol 1,4,5-trisphosphate receptors (IP₃Rs) are intracellular Ca²⁺ channels that link extracellular stimuli to Ca²⁺ signals. Ca²⁺ release from intracellular stores is "quantal": low IP₃ concentrations rapidly release a fraction of the stores. Ca²⁺ release then slows or terminates without compromising responses to further IP₃ additions. The mechanisms are unresolved. Here, we synthesize a high-affinity partial agonist of IP₃Rs and use it to demonstrate that quantal responses do not require heterogenous Ca²⁺ stores. IP₃Rs respond incrementally to IP₃ and close after the initial response to low IP₃ concentrations. Comparing functional responses with IP₃ binding shows that only a tiny fraction of a cell's IP₃Rs mediate incremental Ca²⁺ release; inactivation does not therefore affect most IP₃Rs. We conclude, and test by simulations, that Ca²⁺ signals evoked by IP₃ pulses arise from rapid activation and then inactivation of very few IP₃Rs. This allows IP₃Rs to behave as increment detectors mediating graded Ca²⁺ release.