Quantal Ca(2+) release mediated by very few IP(3) receptors that rapidly inactivate allows graded responses to IP(3)

Inositol 1,4,5-trisphosphate receptors (IP(3)Rs) are intracellular Ca(2+) channels that link extracellular stimuli to Ca(2+) signals. Ca(2+) release from intracellular stores is “quantal”: low IP(3) concentrations rapidly release a fraction of the stores. Ca(2+) release then slows or terminates without compromising responses to further IP(3) additions. The mechanisms are unresolved. Here, we synthesize a high-affinity partial agonist of IP(3)Rs and use it to demonstrate that quantal responses do not require heterogenous Ca(2+) stores. IP(3)Rs respond incrementally to IP(3) and close after the initial response to low IP(3) concentrations. Comparing functional responses with IP(3) binding shows that only a tiny fraction of a cell’s IP(3)Rs mediate incremental Ca(2+) release; inactivation does not therefore affect most IP(3)Rs. We conclude, and test by simulations, that Ca(2+) signals evoked by IP(3) pulses arise from rapid activation and then inactivation of very few IP(3)Rs. This allows IP(3)Rs to behave as increment detectors mediating graded Ca(2+) release.