Loss of cochlear HCO(3)over-bar secretion causes deafness via endolymphatic acidification and inhibition of Ca2+ reabsorption in a Pendred syndrome mouse model
Loss of cochlear HCO(3)over-bar secretion causes deafness via endolymphatic acidification and inhibition of Ca2+ reabsorption in a Pendred syndrome mouse model
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DOI：
10.1152/ajprenal.00487.2006
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发表时间：
2007-05-01
影响因子：
4.2
通讯作者：
Marcus, Daniel C.
中科院分区：
文献类型：
--
作者：
Wangemann, Philine;Nakaya, Kazuhiro;Marcus, Daniel C.
Pendred综合征，以儿童耳聋和青春期后甲状腺肿为特征，由SLC26A4突变引起，SLC26A4编码阴离子交换蛋白。本研究的目的是确定垂垂蛋白的缺失如何导致毛细胞退化和耳聋。采用显微荧光法测定侧膜蛋白功能，听性脑干记录测定听力，共聚焦免疫组织化学方法检测K+和Ca~(2+)通道的表达。用双管离子选择微电极测定耳蜗液pH、Ca~(2+)浓度和内耳电位(EP)。耳蜗腺泡蛋白是一种可穿透甲酸盐和DIDS敏感的阴离子交换器，可能介导HCO3-分泌进入内淋巴。因此，SLC26A4(+/-)小鼠内淋巴比外淋巴液碱性更强，而SLC26A4(-/-)小鼠内淋巴中侧膜蛋白的丢失导致内淋巴酸化。SLC26A4(+/-)小鼠血管纹表达K+通道Kcnj10，并在出生后12天正常听力开始前产生一个小的耳蜗内电位，该小电位和Kcnj10的表达在发育过程中消失，SLC26A4(+/-)小鼠不能获得听力。内淋巴酸化可能通过酸敏感的上皮细胞钙通道TRPV5和TRPV6抑制内淋巴对钙的重吸收。因此，SLC26A4(+/-)小鼠内淋巴液中钙离子浓度升高。这种升高可能会抑制听力所必需的感觉转导，并促进感觉毛细胞的退化。毛细胞的退化关闭了SLC26A4(+/-)小鼠以及可能患有Pendred综合征的人类患者恢复听力正常发育的机会之窗。
Pendred syndrome, characterized by childhood deafness and postpuberty goiter, is caused by mutations of SLC26A4, which codes for the anion exchanger pendrin. The goal of the present study was to determine how loss of pendrin leads to hair cell degeneration and deafness. We evaluated pendrin function by ratiometric microfluorometry, hearing by auditory brain stem recordings, and expression of K+ and Ca2+ channels by confocal immunohistochemistry. Cochlear pH and Ca2+ concentrations and endocochlear potential (EP) were measured with double-barreled ion-selective microelectrodes. Pendrin in the cochlea was characterized as a formate-permeable and DIDS-sensitive anion exchanger that is likely to mediate HCO3- secretion into endolymph. Hence endolymph in Slc26a4(+/-) mice was more alkaline than perilymph, and the loss of pendrin in Slc26a4(-/-) mice led to an acidification of endolymph. The stria vascularis of Slc26a4(+/-) mice expressed the K+ channel Kcnj10 and generated a small endocochlear potential before the normal onset of hearing at postnatal day 12. This small potential and the expression of Kcnj10 were lost during further development, and Slc26a4(+/-) mice did not acquire hearing. Endolymphatic acidification may be responsible for inhibition of Ca2+ reabsorption from endolymph via the acid-sensitive epithelial Ca2+ channels Trpv5 and Trpv6. Hence the endolymphatic Ca2+ concentration was found elevated in Slc26a4(+/-) mice. This elevation may inhibit sensory transduction necessary for hearing and promote the degeneration of the sensory hair cells. Degeneration of the hair cells closes a window of opportunity to restore the normal development of hearing in Slc26a4(+/-) mice and possibly human patients suffering from Pendred syndrome.