Lack of pendrin HCO(3)over-bar transport elevates vestibular endolymphatic [Ca2+] by inhibition of acid-sensitive TRPV5 and TRPV6 channels
Lack of pendrin HCO(3)over-bar transport elevates vestibular endolymphatic [Ca2+] by inhibition of acid-sensitive TRPV5 and TRPV6 channels
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DOI：
10.1152/ajprenal.00432.2006
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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：
Nakaya, Kazuhiro;Harbidge, Donald G.;Marcus, Daniel C.
哺乳动物内耳内淋巴的低Ca2+浓度（[Ca2+]）是正常听力和平衡所必需的。我们报道（Yamauchi等人，Biochem Biophys Res comman 331: 1353- 1357,2005）上皮Ca2+通道TRPV5和TRPV6（瞬时受体电位类型5和6）在前庭系统中表达，TRPV5的表达受到1,25-二羟基维生素D-3的刺激，在肾脏中也有报道。TRPV5/6通道被细胞外酸性pH所抑制。我们在体内测量了Cl-/HCO3-交换器pendin （SLC26A4）敲除小鼠的胞内淋巴pH、[Ca2+]和胞内上皮电位。Slc26a4（-/-）小鼠表现出pH和室内淋巴电位降低和[Ca2+]升高。将大鼠半规管细胞单层原代培养物培养在可透性支架上，分别从顶端和基底外侧测量细胞对Ca-45（2+）的摄取。与1,25-二羟基维生素D-3孵育后，Ca-45（2+）的净吸收率更高。低pH显著抑制净Ca-45（2+）吸收，而碱性pH则促进净Ca-45（2+）吸收，钆、镧和钌红降低了净Ca-45（2+）吸收。这些观察结果支持这样一种观点，即Pendred综合征前庭功能障碍的一个方面是由于腔内酸化和随后抑制trpv5 /6介导的Ca2+吸收导致内淋巴[Ca2+]的病理升高。
The low Ca2+ concentration ([Ca2+]) of mammalian endolymph in the inner ear is required for normal hearing and balance. We reported (Yamauchi et al., Biochem Biophys Res Commun 331: 1353-1357, 2005) that the epithelial Ca2+ channels TRPV5 and TRPV6 (transient receptor potential types 5 and 6) are expressed in the vestibular system and that TRPV5 expression is stimulated by 1,25-dihydroxyvitamin D-3, as also reported in kidney. TRPV5/6 channels are known to be inhibited by extracellular acidic pH. Endolymphatic pH, [Ca2+], and transepithelial potential of the utricle were measured in Cl-/HCO3- exchanger pendrin (SLC26A4) knockout mice in vivo. Slc26a4(-/-) mice exhibit reduced pH and utricular endolymphatic potential and increased [Ca2+]. Monolayers of primary cultures of rat semicircular canal duct cells were grown on permeable supports, and cellular uptake of Ca-45(2+) was measured individually from the apical and basolateral sides. Net uptake of Ca-45(2+) was greater after incubation with 1,25-dihydroxyvitamin D-3. Net Ca-45(2+) absorption was dramatically inhibited by low apical pH and was stimulated by apical alkaline pH. Gadolinium, lanthanum, and ruthenium red reduced apical uptake. These observations support the notion that one aspect of vestibular dysfunction in Pendred syndrome is a pathological elevation of endolymphatic [Ca2+] due to luminal acidification and consequent inhibition of TRPV5/6-mediated Ca2+ absorption.