Venetian Institute of Molecular Medicine, University of Padova, Padua, Italy.
Sci China Life Sci. 2011 Aug;54(8):686-90. doi: 10.1007/s11427-011-4200-z. Epub 2011 Jul 24.
Mammalian cells express four different plasma membrane Ca(2+) ATPases. Two of them (PMCA1 and PMCA4) are expressed ubiquitously, and are considered housekeeping isoforms. Two (PMCA2 and PMCA4) have tissue restricted distribution. They are abundantly expressed in the brain and in nervous tissue-derived cell types. The primary transcripts of all PMCAs undergo alternative splicing, generating a large number of additional isoforms. Splicing occurs at site A, in the N-terminal moiety of the pump, and at site C, within the C-terminal calmodulin binding domain: The pumps are canonical targets of calmodulin stimulation. The site C insertion leads to a truncation of the pump about 50 residues short of the original C-terminal. One of the pumps (PMCA2) has special properties: It displays high activity even in the absence of the natural activator calmodulin, and has a particularly complex pattern of alternative splicing at both sites A and C. A variant of the PMCA2 pump containing an insert at site A and truncated C-terminally is the resident isoform of the pump in the stereocilia of hair cells of the inner ear. It exports Ca(2+) to the endolymph that bathes the stereocilia less efficiently than the full length, non-inserted PMCA2 pump. The proper functioning of hair cells demands the precise maintenance of the Ca(2+) balance between hair cells and the endolymph. Disturbances in the balance affect the process of mechano-electrical transduction, which depends on the ability of the stereociliar bundle to deflect in response to sound waves. The tip links that organize the bundle are formed by the Ca(2+) binding protein cadherin 23 and by protocadherin 15: Disturbances of the Ca(2+) binding by cadherin 23 and/or of the ability of the PMCA2 variant of the stereocilia to export Ca(2+) to the endolymph generate hearing loss phenotypes. Such phenotypes have now been described in mice and humans. In some cases they are linked to mutations of both cadherin 23 and the PMCA2 pump, but in other cases they may be generated by mutations of particular severity in only one of the two proteins. The PMCA2 defect that leads to deafness has now been analyzed molecularly: It affects the long range, unstimulated ability of PMCA2 to export Ca(2+).
哺乳动物细胞表达四种不同的质膜 Ca(2+)ATP 酶。其中两种（PMCA1 和 PMCA4）广泛表达，被认为是管家同工酶。另外两种（PMCA2 和 PMCA4）在组织中分布受限。它们在大脑和神经组织衍生的细胞类型中大量表达。所有 PMCA 的原始转录本都经历选择性剪接，产生大量额外的同工酶。剪接发生在 A 位点，即在泵的 N 端部分，以及 C 位点，在 C 端钙调蛋白结合域内：泵是钙调蛋白刺激的典型靶标。C 位点的插入导致泵在原始 C 端约 50 个残基处截断。其中一种泵（PMCA2）具有特殊性质：即使在没有天然激活剂钙调蛋白的情况下，它也具有很高的活性，并且在 A 位点和 C 位点都具有特别复杂的选择性剪接模式。一种包含 A 位点插入和 C 端截断的 PMCA2 泵变体是内耳毛细胞立体纤毛中泵的固有同工酶。它将 Ca(2+)输出到内淋巴中，其效率低于全长、未插入的 PMCA2 泵。毛细胞的正常功能要求毛细胞和内淋巴之间的 Ca(2+)平衡得到精确维持。平衡的干扰会影响机械-电转导过程，该过程取决于立体纤毛束响应声波偏转的能力。组织纤毛束的顶链接由钙结合蛋白钙粘蛋白 23 和原钙粘蛋白 15 形成：钙粘蛋白 23 的 Ca(2+)结合和/或立体纤毛中 PMCA2 变体将 Ca(2+)输出到内淋巴的能力的干扰会产生听力损失表型。现在已经在小鼠和人类中描述了这种表型。在某些情况下，它们与钙粘蛋白 23 和 PMCA2 泵的突变有关，但在其他情况下，它们可能是由两种蛋白质之一的特定严重突变引起的。导致耳聋的 PMCA2 缺陷现在已经从分子水平上进行了分析：它影响 PMCA2 长距离、无刺激的 Ca(2+)外排能力。
