Critical role of ATP-induced ATP release for Ca2+ signaling in nonsensory cell networks of the developing cochlea.
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+]coscillations 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+]coscillations require oscillations of the cytosolic IP3concentration ([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+]coscillations are governed by Hopf-type bifurcations within the experimental range of [ATP]eand do not require [IP3]coscillations. 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.
Department of Biomedical Sciences, Institute of Cell Biology and Neurobiology, Italian National Research Council, 00015 Monterotondo (RM), Italy.|Department of Physics and Astronomy, University of Padua, 35131 Padua, Italy.|Connexin Structure and Function Unit, Venetian Institute of Molecular Medicine, Foundation for Advanced Biomedical Research, 35129 Padua, Italy.
Federico
F
Ceriani
Department of Biomedical Sciences, Institute of Neuroscience (Padua Section), Italian National Research Council, 35121 Padua, Italy; tullio.pozzan@unipd.it fabio.mammano@cnr.it.|Department of Biomedical Sciences, University of Padua, 35121 Padua, Italy.
Tullio
T
Pozzan
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.|Department of Physics and Astronomy, University of Padua, 35131 Padua, Italy.|Connexin Structure and Function Unit, Venetian Institute of Molecular Medicine, Foundation for Advanced Biomedical Research, 35129 Padua, Italy.|Laboratory of Phenotypic Screening, Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China.
Fabio
F
Mammano
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D020013:Calcium Signaling; D003051:Cochlea / Q000254:growth & development* / Q000378:metabolism*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological
D015544:Inositol 1,4,5-Trisphosphate; D000255:Adenosine Triphosphate
calcium oscillations; calcium waves; cochlear nonsensory cells; connexins; inositol trisphosphate