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Proc Natl Acad Sci U S A. 2016 Nov 15;113(46):E7194-E7201. Epub 2016 Nov 2.

Critical role of ATP-induced ATP release for Ca2+ signaling in nonsensory cell networks of the developing cochlea.

Ceriani F1,2,3, Pozzan T4,5, Mammano F6,2,3,7.

Author information

1
Department of Biomedical Sciences, Institute of Cell Biology and Neurobiology, Italian National Research Council, 00015 Monterotondo (RM), Italy.
2
Department of Physics and Astronomy, University of Padua, 35131 Padua, Italy.
3
Connexin Structure and Function Unit, Venetian Institute of Molecular Medicine, Foundation for Advanced Biomedical Research, 35129 Padua, Italy.
4
Department of Biomedical Sciences, Institute of Neuroscience (Padua Section), Italian National Research Council, 35121 Padua, Italy; tullio.pozzan@unipd.it fabio.mammano@cnr.it.
5
Department of Biomedical Sciences, University of Padua, 35121 Padua, Italy.
6
Department of Biomedical Sciences, Institute of Cell Biology and Neurobiology, Italian National Research Council, 00015 Monterotondo (RM), Italy; tullio.pozzan@unipd.it fabio.mammano@cnr.it.
7
Laboratory of Phenotypic Screening, Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China.

Abstract

Spatially and temporally coordinated variations of the cytosolic free calcium concentration ([Ca2+]c) play a crucial role in a variety of tissues. In the developing sensory epithelium of the mammalian cochlea, elevation of extracellular adenosine trisphosphate concentration ([ATP]e) triggers [Ca2+]c oscillations and propagation of intercellular inositol 1,4,5-trisphosphate (IP3)-dependent Ca2+ waves. What remains uncertain is the relative contribution of gap junction channels and connexin hemichannels to these fundamental mechanisms, defects in which impair hearing acquisition. Another related open question is whether [Ca2+]c oscillations require oscillations of the cytosolic IP3 concentration ([IP3]c) in this system. To address these issues, we performed Ca2+ imaging experiments in the lesser epithelial ridge of the mouse cochlea around postnatal day 5 and constructed a computational model in quantitative adherence to experimental data. Our results indicate that [Ca2+]c oscillations are governed by Hopf-type bifurcations within the experimental range of [ATP]e and do not require [IP3]c oscillations. The model replicates accurately the spatial extent and propagation speed of intercellular Ca2+ waves and predicts that ATP-induced ATP release is the primary mechanism underlying intercellular propagation of Ca2+ signals. The model also uncovers a discontinuous transition from propagating regimes (intercellular Ca2+ wave speed > 11 μm⋅s-1) to propagation failure (speed = 0), which occurs upon lowering the maximal ATP release rate below a minimal threshold value. The approach presented here overcomes major limitations due to lack of specific connexin channel inhibitors and can be extended to other coupled cellular systems.

KEYWORDS:

calcium oscillations; calcium waves; cochlear nonsensory cells; connexins; inositol trisphosphate

PMID:
27807138
PMCID:
PMC5135323
DOI:
10.1073/pnas.1616061113
[Indexed for MEDLINE]
Free PMC Article

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