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+ ]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.