Lack of Oncomodulin Increases ATP-Dependent Calcium Signaling and Susceptibility to Noise in Adult Mice

Abstract

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 fromOcm-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 inOcm+/+andOcm-/-mice but the loss of hearing was permanent forOcm-/-mice. However, whileOcm+/+fully recovered their hearing 2 weeks after noise exposure,Ocm-/-mice showed permanent threshold shifts. Using a genetically encoded Ca2+sensor (GCaMP6s) expressed inOcm+/+andOcm-/-OHCs, we found that chronic noise exposure (95 dB SPL, 9 hrs) increased ATP-induced Ca2+signaling inOcm-/-OHCs compared toOcm+/+OHCs. Chronic noise exposures also caused higher hearing threshold shifts inOcm-/-mice. Prior to noise exposure, P2X2 expression was already upregulated inOcm-/-mice compared toOcm+/+mice. Following chronic noise, P2X2 receptors were upregulated in theOcm+/+cochlea but not in theOcm-/-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 theOcm-/-mice.