Research ArticleCell Biology

Hindered cytoplasmic diffusion of inositol trisphosphate restricts its cellular range of action

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Sci. Signal.  08 Nov 2016:
Vol. 9, Issue 453, pp. ra108
DOI: 10.1126/scisignal.aag1625

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A new paradigm for IP3 signaling

Receptors that activate phospholipase C generate the second messenger inositol trisphosphate (IP3). IP3 stimulates calcium release from the endoplasmic and sarcoplasmic reticulum, thereby shaping calcium signals in cells. Dickinson et al. triggered the focal release of IP3 in animal cells and measured calcium “puffs”—intense, localized increases in calcium released from the endoplasmic reticulum. They found that IP3 diffuses much more slowly within cells than had been originally measured in vitro using oocyte cytoplasmic extracts. Thus, rather than functioning as a global cellular signal, IP3 can produce local signals, which increases the complexity of information that can be encoded by cells in response to stimuli that activate receptors that generate this second messenger.

Abstract

The range of action of intracellular messengers is determined by their rates of diffusion and degradation. Previous measurements in oocyte cytoplasmic extracts indicated that the Ca2+-liberating second messenger inositol trisphosphate (IP3) diffuses with a coefficient (~280 μm2 s−1) similar to that in water, corresponding to a range of action of ~25 μm. Consequently, IP3 is generally considered a “global” cellular messenger. We reexamined this issue by measuring local IP3-evoked Ca2+ puffs to monitor IP3 diffusing from spot photorelease in neuroblastoma cells. Fitting these data by numerical simulations yielded a diffusion coefficient (≤10 μm2 s−1) about 30-fold slower than that previously reported. We propose that diffusion of IP3 in mammalian cells is hindered by binding to immobile, functionally inactive receptors that were diluted in oocyte extracts. The predicted range of action of IP3 (<5 μm) is thus smaller than the size of typical mammalian cells, indicating that IP3 should better be considered as a local rather than a global cellular messenger.

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