Oncomodulin (OCM) uniquely regulates calcium signaling in neonatal cochlear outer hair cells
Oncomodulin (OCM) uniquely regulates calcium signaling in neonatal cochlear outer hair cells
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DOI：
10.1101/2022.03.03.482327
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发表时间：
2022-03
期刊：
影响因子：
4
通讯作者：
Kaitlin Murtha;Yang Yang-Yang;F. Ceriani;J. Jeng;Leslie K. Climer;F. Jones;Jack Charles;Sai K. Devana;Aubrey J. Hornak;W. Marcotti;D. Simmons
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文献类型：
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作者：
Kaitlin Murtha;Yang Yang-Yang;F. Ceriani;J. Jeng;Leslie K. Climer;F. Jones;Jack Charles;Sai K. Devana;Aubrey J. Hornak;W. Marcotti;D. Simmons
在耳蜗外毛细胞中，由钙离子通道、泵和钙结合蛋白(CaBP)组成的网络调节着游离钙离子的定位、扩散和大小。在出生后的早期发育中，毛细胞表达三种重要的移动性EF-Hand CaBP：oncomodrin(OCm)、α-parvalbrain(APV)和Sorin。我们之前已经证明，OCM(OCM-/-)的缺失会导致幼年成年小鼠进行性耳蜗功能障碍。在这里，我们表明，钙信号的变化开始于OCM-/-小鼠出生后发育的早期。虽然突变的OHC与对照组相比表现出正常的电生理特征，但它们的细胞内钙信号发生了变化。OCM在出生后第3天(P3)开始表达，导致KCl诱导的毛细胞钙瞬变发生发育变化，并导致KCl1诱导的钙瞬变慢于OCM-/-窝产仔细胞。我们在动物模型和培养细胞中比较了OCM与其他CaBP的缓冲动力学。在OCM和APV(OCM-/-；APV-/-)的双重敲除中，突变的内质网表现出更快的钙动力学，提示APV可能也参与了出生后早期的钙信号。在转染的HEK293T细胞中，OCM比APV或Sorcin更能减缓钙动力学。我们的结论是，OCM通过降低OHC和HEK293T细胞中自由可用[Ca~(2+)]i的量来控制细胞内的钙环境。我们认为，OCM通过其无与伦比的钙缓冲能力，在形成早期OHC钙信号的发展中起着重要作用。
In cochlear outer hair cells (OHCs), a network of Ca2+ channels, pumps and Ca2+-binding proteins (CaBPs) regulates the localization, spread, and magnitude of free Ca2+ ions. During early postnatal development, OHCs express three prominent mobile EF-hand CaBPs: oncomodulin (OCM), α-parvalbumin (APV) and sorcin. We have previously shown that deletion of Ocm (Ocm-/-) gives rise to progressive cochlear dysfunction in young adult mice. Here, we show that changes in Ca2+ signaling begin early in postnatal development of Ocm-/- mice. While mutant OHCs exhibit normal electrophysiological profiles compared to controls, their intracellular Ca2+ signaling is altered. The onset of OCM expression at postnatal day 3 (P3) causes a developmental change in KCl-induced Ca2+ transients in OHCs and leads to slower KCl-induced Ca2+ transients than those elicited in cells from Ocm-/- littermates. We compared OCM buffering kinetics with other CaBPs in animal models and cultured cells. In a double knockout of Ocm and Apv (Ocm-/-;Apv-/-), mutant OHCs show even faster Ca2+ kinetics, suggesting that APV may also contribute to early postnatal Ca2+ signaling. In transfected HEK293T cells, OCM slows Ca2+ kinetics more so than either APV or sorcin. We conclude that OCM controls the intracellular Ca2+ environment by lowering the amount of freely available [Ca2+]i in OHCs and in transfected HEK293T cells. We propose that OCM plays an important role in shaping the development of early OHC Ca2+ signals through its inimitable Ca2+ buffering capacity.