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

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.