Abstract
Plasma membrane Ca2+-ATPase isoform 2 (PMCA2) exhibits a highly restricted tissue distribution, suggesting that it serves more specialized physiological functions than some of the other isoforms. A unique role in hearing is indicated by the high levels of PMCA2 expression in cochlear outer hair cells and spiral ganglion cells. To analyze the physiological role of PMCA2 we used gene targeting to produce PMCA2-deficient mice. Breeding of heterozygous mice yielded live homozygous mutant offspring. PMCA2-null mice grow more slowly than heterozygous and wild-type mice and exhibit an unsteady gait and difficulties in maintaining balance. Histological analysis of the cerebellum and inner ear of mutant and wild-type mice revealed that null mutants had slightly increased numbers of Purkinje neurons (in which PMCA2 is highly expressed), a decreased thickness of the molecular layer, an absence of otoconia in the vestibular system, and a range of abnormalities of the organ of Corti. Analysis of auditory evoked brainstem responses revealed that homozygous mutants were deaf and that heterozygous mice had a significant hearing loss. These data demonstrate that PMCA2 is required for both balance and hearing and suggest that it may be a major source of the calcium used in the formation and maintenance of otoconia.
Highlights
Histological and Morphometric Analyses of Cerebellum—Because PMCA2 is expressed at high levels in Purkinje neurons [15], we evaluated the morphology of the cerebellum
The objectives of this study were to develop a Pmca2-deficient mouse and to analyze its phenotype to better understand the physiological functions of this isoform in vivo
Because in situ hybridization studies have shown that PMCA2 is expressed at high levels in Purkinje neurons [15], we considered the possibility that the ataxia was because of a cerebellar defect
Summary
Variants of PMCA1 and PMCA4 are expressed in many different tissues and cell types, whereas variants of PMCA2 and PMCA3 exhibit a highly restricted distribution [5, 8, 12] This suggests that specific isoforms and splice variants serve different physiological functions. The observation that PMCA2 is the predominant isoform in outer hair cells [16] suggests that it might be the isoform that is expressed at high levels in stereocilia [17], which comprise hair bundles, the sensory organelles that mediate mechanoelectrical transduction by hair cells of both the vestibular and auditory systems [18, 19].
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