Spatially and temporally coordinated variations of the cytosolic free calcium concentration ([Ca(2+)]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 [Ca(2+)]c oscillations and propagation of intercellular inositol 1,4,5-trisphosphate (IP3)-dependent Ca(2+) 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 [Ca(2+)]c oscillations require oscillations of the cytosolic IP3 concentration ([IP3]c) in this system. To address these issues, we performed Ca(2+) 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 [Ca(2+)]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 Ca(2+) waves and predicts that ATP-induced ATP release is the primary mechanism underlying intercellular propagation of Ca(2+) signals. The model also uncovers a discontinuous transition from propagating regimes (intercellular Ca(2+) 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.

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

CERIANI, FEDERICO;POZZAN, TULLIO;MAMMANO, FABIO
2016

Abstract

Spatially and temporally coordinated variations of the cytosolic free calcium concentration ([Ca(2+)]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 [Ca(2+)]c oscillations and propagation of intercellular inositol 1,4,5-trisphosphate (IP3)-dependent Ca(2+) 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 [Ca(2+)]c oscillations require oscillations of the cytosolic IP3 concentration ([IP3]c) in this system. To address these issues, we performed Ca(2+) 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 [Ca(2+)]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 Ca(2+) waves and predicts that ATP-induced ATP release is the primary mechanism underlying intercellular propagation of Ca(2+) signals. The model also uncovers a discontinuous transition from propagating regimes (intercellular Ca(2+) 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.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11577/3208579
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