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Abstract
Calcium homeostasis is regulated, in part, by the plasma membrane calcium ATPases (PMCAs), which are encoded by a family of alternatively spliced genes. Isoform 2 (PMCA2) is found at high levels in brain and heart, with lower levels in other tissues, including the kidney and inner ear. To identify the physiological roles of PMCA2, this gene was ablated in mice via homologous recombination. Mice were born in a normal Mendelian ratio and were viable. In vivo performance measurements suggested that PMCA2 does not play a major role in cardiac muscle contraction. Analysis of urinary calcium concentration suggested that the absence of PMCA2 may impair calcium reabsorption in the renal nephron. A thinning of the molecular layer and a slight increase in the number of Purkinje cells, in which PMCA2 is highly expressed, were observed by histological analysis of cerebella of Pmca2−/− mice.
The major phenotypes of Pmca2− deficient mice involved the inner ear. Beginning twelve days post partum, Pmca2 −/− mice displayed a balance deficit that is due, in large part, to the absence of otoconia in the utricle and saccule, gravity-sensing organs in the inner ear. Pmca2−/− mice were deaf and exhibited a spectrum of cochlear histopathologies, including the degradation of the major cell types necessary for the detection of sound. Depending on genetic background, Pmca2+/mice heard normally or had hearing thresholds that were 30–50 dB greater than Pmca2 +/+ littermates. PMCA2 is highly expressed in outer hair cells, and the cytoplasmic calcium concentration in outer hair cells rises following acoustic overstimulation, suggesting that PMCA2 activity may play a role in the response to sound exposure. Pmca2−/− mice had large, permanent increases in hearing thresholds following noise exposure, indicating that they were more susceptible to noise induced hearing loss than Pmca2+/+ littermates. These data indicate that PMCA2 plays a critical role in balance and hearing.
