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

Ana M Rossi,Geneviève Dupont,Taufiq Rahman,Barry V.L Potter,Andrew M Riley,Colin W Taylor

doi:10.1016/j.celrep.2021.109932

Ana M Rossi, Geneviève Dupont + Show 4 more

Open Access

https://doi.org/10.1016/j.celrep.2021.109932

Copy DOI

Abstract

SummaryInositol 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.

Highlights

Inositol 1,4,5-trisphosphate (IP3) links receptors in the plasma membrane to Ca2+ release from the endoplasmic reticulum (ER) through IP3 receptors (IP3Rs), which are intracellular Ca2+ channels (Berridge, 2016)
Submaximal IP3 concentrations rapidly released a smaller fraction of the stores, after which there was no further effect of IP3 on the rate of Ca2+ release or its effect was much reduced (Figure 1D)
Quantal Ca2+ release is an unusual feature of IP3Rs, first described in 1989 (Muallem et al, 1989), but never adequately explained (Yamashita, 2006)

Summary

Introduction

Inositol 1,4,5-trisphosphate (IP3) links receptors in the plasma membrane to Ca2+ release from the endoplasmic reticulum (ER) through IP3 receptors (IP3Rs), which are intracellular Ca2+ channels (Berridge, 2016). This redistribution of Ca2+ from the ER generates cytosolic Ca2+ signals, transfers Ca2+ to other organelles, and stimulates store-operated Ca2+ entry. Dispersed clusters of channels constrain regenerative propagation of Ca2+ signals between them (Rıos, 2018), and inhibition of IP3Rs (and RyRs) by increased cytosolic free Ca2+ concentration ([Ca2+]c) may contribute to terminating Ca2+ release, but it may not be the only mechanism (Wiltgen et al, 2014)

Methods

Results

Conclusion