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

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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.

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Algorithms used to generate SD fluctuation images from Ca2+ image recordings are provided in the Supplementary file 1.

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Jeffrey T Lock

Department of Neurobiology and Behavior, University of California, Irvine, Irvine, United States

For correspondence
lockj@uci.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-1522-3189
Ian Parker

Department of Physiology and Biophysics, University of California, Irvine, Irvine, United States

Competing interests
The authors declare that no competing interests exist.

Funding

National Institute of General Medical Sciences (R37 GM048071)

Ian Parker

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.