期刊
JOURNAL OF NEUROPHYSIOLOGY
卷 103, 期 4, 页码 1969-1977出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/jn.01057.2009
关键词
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资金
- National Institute on Deafness and Other Communication Disorders [DC-005983, DC-000141, DC-007592, DC-010386]
- NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS [P30DC005983, R01DC007592, R01DC010386] Funding Source: NIH RePORTER
Wu T, Lv P, Kim HJ, Yamoah EN, Nuttall AL. Effect of salicylate on KCNQ4 of the guinea pig outer hair cell. J Neurophysiol 103: 1969-1977, 2010. First published February 10, 2010; doi: 10.1152/jn.01057.2009. Salicylate causes a moderate hearing loss and tinnitus in humans at high-dose levels. Salicylate-induced hearing loss has been attributed to impaired sound amplification by outer hair cells (OHCs) through its direct action on the OHC motility sensor and/or motor. However, there is a disparity of salicylate concentrations between the clinical and animal studies, i.e., extremely high extracellular concentrations of salicylate (from 1 to 10 mM) is required to produce a significant reduction of electromotility in animal studies. Such concentrations are above the clinical/physiological range for humans. Here, we showed that clinical/physiological concentration range of salicylate caused concentration-dependent and reversible reductions in I-K,I-n (KCNQ4) and subsequent depolarization of OHCs. Salicylate reduced the maximal tail current of the activation curve of I-K,I-n without altering the voltage-sensitivity (V-half). The salicylate-induced reduction of I-K,I-n was almost completely blocked by linopirdine (0.1 mM) and BaCl2 (10 mM). Consistent with the finding in OHCs, salicylate significantly reduced KCNQ4-mediated current expressed in Chinese hamster ovarian (CHO) cells by comparable amplitude to OHCs without significantly shifting V-half. Nonstationary fluctuation analysis shows that salicylate significantly reduced the estimated single-channel current amplitude and numbers. Intracellular Ca2+ elevation resulting from cytoplasmic acidosis also contributes to the current reduction of I-K,I-n (KCNQ4) of OHCs. These results indicate a different model for the salicylate-induced hearing loss through the reduction of KCNQ4 and subsequent depolarization of OHCs, which reduces the driving force for transduction current and electromotility. The major mechanism underlying the reduction of I-K,I-n ( KCNQ4) is the direct blocking action of salicylate on KCNQ4.
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