Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 46, Pages E7194-E7201Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1616061113
Keywords
inositol trisphosphate; calcium waves; calcium oscillations; cochlear nonsensory cells; connexins
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Funding
- Fondazione Telethon [GGP13114]
- Italian National Research Council [DSB.AD009.001.004/INVECCHIAMENTO]
- Italian Ministry of University and Research [FIRB-RBAP11X42L]
- University of Padua [CPDR132235]
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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 mu m.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.
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