Oncomodulin regulates calcium signaling in cochlear outer hair cells and protects hearing from noise.

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Hearing loss is one of the most common impairments that can be caused by many factors, such as loud noise, aging, disease, and genetic defects. In the mammalian cochlea, two specialized sensory cell types, inner hair cells (IHCs) and outer hair cells (OHCs), are involved in the transduction of sound into electrical responses. Calcium (Ca2+) plays an essential role in the process of mechanotransduction, amplification, and synaptic transmission in cochlear sensory hair cells. Tight regulation and control of Ca2+ are fundamentally important to the function of the cochlea during development and in adults. The maintenance of Ca2+ homeostasis in OHCs involves a multitude of calcium-binding proteins (CaBPs) and Ca2+ transporters. Oncomodulin (OCM), a small EF-hand CaBP, is expressed predominantly by OHCs. A recent study showed that Ocm knockout (Ocm-/-) mice exhibit progressive hearing loss starting at 1-2 months and are deaf by 4 months. However, the role of OCM in cochlear development and the maintenance of normal hair cell function remains unclear. Here, we hypothesize that the absence of OCM alters calcium signaling in both immature and mature OHCs. We first investigated the changes in Ca2+ signaling that begin early in the postnatal development of Ocm-/- mice in CBA/CaH background. At postnatal day 3 (P3), the lack of OCM decreased the Ca2+ transients in OHCs induced by KCl. Using both OHCs and transfected HEK293T cells, we found that OCM slowed Ca2+ kinetics more so than other CaBPs such as α-parvalbumin or sorcin. To measure the Ca2+ signaling in the cochlea, we endogenously expressed a genetically encoded Ca2+ sensor (Atoh1-GCaMP6s) in wild-type (Ocm+/+) and Ocm-/- mice. We observed an increased spontaneous Ca2+ activity and upregulation of purinergic receptors, such as P2X2 in Ocm-/- OHCs immediately following birth. The afferent synaptic maturation was delayed in the Ocm-/- cochlea during development. In adult mice, the lack of OCM increased the susceptibility to noise and altered ATP-induced Ca2+ activity by upregulating P2X2 expression. We conclude that OCM modulates the Ca2+ signaling network in both neonatal and mature OHCs, changes the maturation of OHC afferent innervation, and leads to deleterious consequences such as progressive hearing loss and increased vulnerability to noise.

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