Lack of Oncomodulin Increases ATP-Dependent Calcium Signaling and Susceptibility to Noise in Adult Mice
Tight regulation of Ca2+ is crucial for the function of cochlear outer hair cells (OHCs). Dysregulation of Ca2+ homeostasis in OHCs is associated with impaired hearing function and contributes to increased vulnerability to environmental insults, such as noise exposure. Ca2+ signaling in developing OHCs can be modulated by oncomodulin (OCM), an EF-hand calcium-binding protein. Here, we investigated whether the lack of OCM disrupts the control of intracellular Ca2+ in mature OHCs, and influences vulnerability to noise. Using young adult CBA/CaJ mice, we found that OHCs from Ocm-knockout (Ocm-/-) mice exhibited normal biophysical profiles and electromotile responses compared to littermate control OHCs. Moderate noise exposure (95 dB SPL, 2 hrs) caused temporary hearing threshold shifts in Ocm+/+ and Ocm-/- mice but the loss of hearing was permanent for Ocm-/- mice. However, while Ocm+/+ fully recovered their hearing 2 weeks after noise exposure, Ocm-/- mice showed permanent threshold shifts. Using a genetically encoded Ca2+ sensor (GCaMP6s) expressed in Ocm+/+ and Ocm-/- OHCs, we found that chronic noise exposure (95 dB SPL, 9 hrs) increased ATP-induced Ca2+ signaling in Ocm-/- OHCs compared to Ocm+/+ OHCs. Chronic noise exposures also caused higher hearing threshold shifts in Ocm-/- mice. Prior to noise exposure, P2X2 expression was already upregulated in Ocm-/- mice compared to Ocm+/+ mice. Following chronic noise, P2X2 receptors were upregulated in the Ocm+/+ cochlea but not in the Ocm-/- cochlea, which retains their pre-noise high expression level. We propose that the lack of OCM increases susceptibility to noise. Increased purinergic signaling and dysregulation of cytosolic Ca2+ homeostasis could contribute to early onset hearing loss in the Ocm-/- mice.