IP3 mediated global Ca2+ signals arise through two temporally and spatially distinct modes of Ca2+ release.

Jeffrey T Lock,Ian Parker

doi:10.7554/elife.55008

Abstract

The 'building-block' model of inositol trisphosphate (IP3)-mediated Ca2+ liberation posits that cell-wide cytosolic Ca2+ signals arise through coordinated activation of localized Ca2+ puffs generated by stationary clusters of IP3 receptors (IP3Rs). Here, we revise this hypothesis, applying fluctuation analysis to resolve Ca2+ signals otherwise obscured during large Ca2+ elevations. We find the rising phase of global Ca2+ signals is punctuated by a flurry of puffs, which terminate before the peak by a mechanism involving partial ER Ca2+ depletion. The continuing rise in Ca2+, and persistence of global signals even when puffs are absent, reveal a second mode of spatiotemporally diffuse Ca2+ signaling. Puffs make only small, transient contributions to global Ca2+ signals, which are sustained by diffuse release of Ca2+ through a functionally distinct process. These two modes of IP3-mediated Ca2+ liberation have important implications for downstream signaling, imparting spatial and kinetic specificity to Ca2+-dependent effector functions and Ca2+ transport.

Highlights

Cytosolic Ca2+ signals generated by the liberation of Ca2+ ions sequestered in the endoplasmic reticulum (ER) through inositol trisphosphate receptor (IP3R) channels regulate ubiquitous cellular processes as diverse as gene transcription, secretion, mitochondrial energetics, electrical excitability and fertilization (Clapham, 2007; Berridge et al, 2000)
In light of the resemblance between the inverted U relationship between puff activity and Ca2+ level (Figure 3) and the well-known bell-shaped curve for biphasic modulation of IP3 receptors (IP3Rs) channel activation by Ca2+(Iino, 1990; Bezprozvanny et al, 1991), we considered whether the suppression of puff activity during global elevations might result because IP3Rs became inhibited by rising cytosolic Ca2+ levels
Ca2+ puffs are transient, localized elevations in cytosolic Ca2+ that arise from concerted opening of small numbers of IP3Rs clustered at fixed intracellular sites (Parker and Yao, 1991; Thillaiappan et al, 2017)

Summary

Introduction

Cytosolic Ca2+ signals generated by the liberation of Ca2+ ions sequestered in the endoplasmic reticulum (ER) through inositol trisphosphate receptor (IP3R) channels regulate ubiquitous cellular processes as diverse as gene transcription, secretion, mitochondrial energetics, electrical excitability and fertilization (Clapham, 2007; Berridge et al, 2000). Cells achieve such unique repertories of Ca2+-dependent functions by generating a hierarchy of cytosolic Ca2+ signals with markedly different spatial scales and temporal durations, ranging from brief, localized Ca2+ transients called puffs (Parker and Yao, 1991; Yao et al, 1995) to larger and more prolonged Ca2+ elevations that engulf the cell. Ca2+ diffusing from one open channel may trigger the opening of adjacent channels, with self-reinforcing CICR

Methods

Results

Conclusion