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PLoS One. 2014 Jan 27;9(1):e86410. doi: 10.1371/journal.pone.0086410. eCollection 2014.

Phospholipase C-β1 and β4 contribute to non-genetic cell-to-cell variability in histamine-induced calcium signals in HeLa cells.

Author information

1
Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute, Wako, Japan.
2
Laboratory of Genome and Biosignal, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
3
Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute, Wako, Japan ; Calcium Oscillation Project, ICORP-SORST, Japan Science and Technology Agency, Kawaguchi, Japan ; Laboratory for Behavioral Genetics, RIKEN Brain Science Institute, Wako, Japan.
4
Laboratory for Developmental Neurobiology, RIKEN Brain Science Institute, Wako, Japan ; Calcium Oscillation Project, ICORP-SORST, Japan Science and Technology Agency, Kawaguchi, Japan.

Abstract

A uniform extracellular stimulus triggers cell-specific patterns of Ca(2+) signals, even in genetically identical cell populations. However, the underlying mechanism that generates the cell-to-cell variability remains unknown. We monitored cytosolic inositol 1,4,5-trisphosphate (IP3) concentration changes using a fluorescent IP3 sensor in single HeLa cells showing different patterns of histamine-induced Ca(2+) oscillations in terms of the time constant of Ca(2+) spike amplitude decay and the Ca(2+) oscillation frequency. HeLa cells stimulated with histamine exhibited a considerable variation in the temporal pattern of Ca(2+) signals and we found that there were cell-specific IP3 dynamics depending on the patterns of Ca(2+) signals. RT-PCR and western blot analyses showed that phospholipase C (PLC)-β1, -β3, -β4, -γ1, -δ3 and -ε were expressed at relatively high levels in HeLa cells. Small interfering RNA-mediated silencing of PLC isozymes revealed that PLC-β1 and PLC-β4 were specifically involved in the histamine-induced IP3 increases in HeLa cells. Modulation of IP3 dynamics by knockdown or overexpression of the isozymes PLC-β1 and PLC-β4 resulted in specific changes in the characteristics of Ca(2+) oscillations, such as the time constant of the temporal changes in the Ca(2+) spike amplitude and the Ca(2+) oscillation frequency, within the range of the cell-to-cell variability found in wild-type cell populations. These findings indicate that the heterogeneity in the process of IP3 production, rather than IP3-induced Ca(2+) release, can cause cell-to-cell variability in the patterns of Ca(2+) signals and that PLC-β1 and PLC-β4 contribute to generate cell-specific Ca(2+) signals evoked by G protein-coupled receptor stimulation.

PMID:
24475116
PMCID:
PMC3903530
DOI:
10.1371/journal.pone.0086410
[Indexed for MEDLINE]
Free PMC Article

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