Gap Junction-Mediated Intercellular Communication of cAMP Prevents CDDP-Induced Ototoxicity via cAMP/PKA/CREB Pathway

• Published in: International journal of molecular sciences Vol. 22; no. 12; p. 6327
• Main Authors: Kim, Yeon Ju, Lee, Jin-Sol, Kim, Hantai, Jang, Jeong Hun, Choung, Yun-Hoon
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 13-06-2021; MDPI
• Subjects: A549 Cells; Adenosine; Adenosine monophosphate; all-trans retinoic acid; Animal models; Animals; Apoptosis; cAMP; Cell activation; Cell Communication - drug effects; Cell cycle; Cell death; Cell Death - drug effects; Cell signaling; Chemotherapy; Cisplatin; Cisplatin - adverse effects; Cochlea; Colforsin - pharmacology; Colforsin - therapeutic use; Connexin 26 - metabolism; Cyclic AMP - metabolism; Cyclic AMP response element-binding protein; Cyclic AMP Response Element-Binding Protein - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; Cytotoxicity; Drug dosages; Ears & hearing; Forskolin; gap junction; Gap junctions; Gap Junctions - drug effects; Gap Junctions - metabolism; Hair Cells, Auditory - metabolism; Hearing loss; Hearing Loss - chemically induced; Hearing Loss - drug therapy; Hearing Loss - prevention & control; HeLa Cells; Humans; Kinases; Mice; Organ of Corti; Ototoxicity; Ototoxicity - metabolism; Phosphorylation; Potassium; Protective Agents - pharmacology; Protein kinase A; Proteins; Quinoline; Rats; Rats, Sprague-Dawley; Retinoic acid; Signal Transduction - drug effects; Sodium-Potassium-Exchanging ATPase - metabolism; Spiral Ganglion - drug effects; Spiral Ganglion - pathology; Tretinoin - pharmacology; Tretinoin - therapeutic use; all-trans retinoic acid; forskolin; gap junction; cAMP; cisplatin; ototoxicity
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22126327

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.