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

• Published in: Cell reports (Cambridge) 2021-11, Vol.37 (5), p.109932-109932, Article 109932
• Main Authors: Rossi, Ana M., Riley, Andrew M., Dupont, Geneviève, Rahman, Taufiq, Potter, Barry V.L., Taylor, Colin W.
• Format: Article
• Language: English
• Subjects: Ca2+ signaling; endoplasmic reticulum; intracellular Ca2+ stores; IP3 receptor; IP3 receptor antagonist; partial agonist; quantal Ca2+ release; receptor inactivation
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109932

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. [Display omitted] •IP3 evokes quantal Ca2+ release from the endoplasmic reticulum•IP3 receptors rapidly activate and then inactivate•Submaximal responses to IP3 require activation of very few IP3 receptors•Rapid activation and inactivation of very few IP3Rs allow incremental responses to IP3 Rossi et al. define mechanisms for IP3-evoked quantal Ca2+ release that reconcile response termination with undiminished sensitivity to further IP3 additions. They show that responses require very few IP3 receptors that rapidly open and then inactivate, allowing graded responses despite the ability of IP3 receptors to propagate regenerative Ca2+ signals.