Abstract
In the cochlea, non-sensory supporting cells are directly connected to adjacent supporting cells via gap junctions that allow the exchange of small molecules. We have previously shown that the pharmacological regulation of gap junctions alleviates cisplatin (CDDP)-induced ototoxicity in animal models. In this study, we aimed to identify specific small molecules that pass through gap junctions in the process of CDDP-induced auditory cell death and suggest new mechanisms to prevent hearing loss. We found that the cyclic adenosine monophosphate (cAMP) inducer forskolin (FSK) significantly attenuated CDDP-induced auditory cell death in vitro and ex vivo. The activation of cAMP/PKA/CREB signaling was observed in organ of Corti primary cells treated with FSK, especially in supporting cells. Co-treatment with gap junction enhancers such as all-trans retinoic acid (ATRA) and quinoline showed potentiating effects with FSK on cell survival via activation of cAMP/PKA/CREB. In vivo, the combination of FSK and ATRA was more effective for preventing ototoxicity compared to either single treatment. Our study provides the new insight that gap junction-mediated intercellular communication of cAMP may prevent CDDP-induced ototoxicity.
Highlights
The sensory epithelium of the inner ear contains mechanosensory cells, known as hair cells (HCs), each of which is surrounded by non-sensory supporting cells (SCs)
We found that FSK treatment reduced the loss of HCs with CDDP treatment in the organotypic culture of OC. cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP-response element binding protein (CREB) signaling initiates a downstream pathway that regulates various cellular responses, including survival, proliferation, metabolism, cell cycle, and ion channels [16]
We examined the expression of p-CREB, p-PKA, Cx26, and Na+ /K+ -ATPase in cochlear tissues to investigate whether the preventive effects of FSK and all-trans retinoic acid (ATRA) on CDDPinduced ototoxicity were mediated by cAMP and gap junction functions
Summary
The sensory epithelium of the inner ear contains mechanosensory cells, known as hair cells (HCs), each of which is surrounded by non-sensory supporting cells (SCs). Gap junctions, consisting of connexin (Cx) proteins, are specialized intercellular channels between adjacent cells that allow the passage of small molecules, including second messengers, ions, and metabolites of up to 1 kDa. In the inner ear, the elaborate network of gap junctions is essential to hearing function due to its cycling of potassium ions to maintain high endocochlear potential and fluid homeostasis [1,2]. The essential role of gap junctions in hearing has been shown in numerous genetic analyses and functional linkage studies between the mutation of. Fibrocytes in the lateral wall (LW) of the cochlea are involved in potassium ion exchange via gap junctions during auditory transduction. Despite the significance of gap junctions to hearing function, little is known about the biological molecules that are communicated through cochlear gap junction networks and affect hearing loss caused by external sources of damage, including ototoxic drugs and noise
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