Significance: Transient receptor potential (TRP) channels are cation-gated channels that serve as detectors of various sensory modalities, such as pain, heat, cold, and taste. These channels are expressed in the inner ear, suggesting that they could also contribute to the perception of sound. This review provides more details on the different types of TRP channels that have been identified in the cochlea to date, focusing on their cochlear distribution, regulation, and potential contributions to auditory functions. Recent Advances: To date, the effect of TRP channels on normal cochlear physiology in mammals is still unclear. These channels contribute, to a limited extent, to normal cochlear physiology such as the hair cell mechanoelectrical transduction channel and strial functions. More detailed information on a number of these channels in the cochlea awaits future studies. Several laboratories focusing on TRPV1 channels have shown that they are responsive to cochlear stressors, such as ototoxic drugs and noise, and regulate cytoprotective and/or cell death pathways. TRPV1 expression in the cochlea is under control of oxidative stress (produced primarily by NOX3 NADPH oxidase) as well as STAT1 and STAT3 transcription factors, which differentially modulate inflammatory and apoptotic signals in the cochlea. Inhibition of oxidative stress or inflammation reduces the expression of TRPV1 channels and protects against cochlear damage and hearing loss. Critical Issues: TRPV1 channels are activated by both capsaicin and cisplatin, which produce differential effects on the inner ear. How these differential actions are produced is yet to be determined. It is clear that TRPV1 is an essential component of cisplatin ototoxicity as knockdown of these channels protects against hearing loss. In contrast, activation of TRPV1 by capsaicin protected against subsequent hearing loss induced by cisplatin. The cellular targets that are influenced by these two drugs to account for their differential profiles need to be fully elucidated. Furthermore, the potential involvement of different TRP channels present in the cochlea in regulating cisplatin ototoxicity needs to be determined. Future Directions: TRPV1 has been shown to mediate the entry of aminoglycosides into the hair cells. Thus, novel otoprotective strategies could involve designing drugs to inhibit entry of aminoglycosides and possibly other ototoxins into cochlear hair cells. TRP channels, including TRPV1, are expressed on circulating and resident immune cells. These receptors modulate immune cell functions. However, whether they are activated by cochlear stressors to initiate cochlear inflammation and ototoxicity needs to be determined. A better understanding of the function and regulation of these TRP channels in the cochlea could enable development of novel treatments for treating hearing loss. Antioxid. Redox Signal. 36, 1158-1170.
Keywords: NADPH oxidases; cochlea; cytokines; free radicals; hearing loss; inflammation; nitric oxide; ototoxicity; receptors; transcription factors.