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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.

Original publication

DOI

10.1016/j.celrep.2021.109932

Type

Journal article

Journal

Cell Rep

Publication Date

02/11/2021

Volume

37

Keywords

Ca(2+) signaling, IP(3) receptor, IP(3) receptor antagonist, endoplasmic reticulum, intracellular Ca(2+) stores, partial agonist, quantal Ca(2+) release, receptor inactivation, Animals, Calcium, Calcium Signaling, Chickens, Drug Partial Agonism, Endoplasmic Reticulum, HEK293 Cells, Humans, Inositol 1,4,5-Trisphosphate, Inositol 1,4,5-Trisphosphate Receptors, Inositol Phosphates, Time Factors