Disease relevance of Atp2b2

• Our results reveal an epistatic relationship between the mdfw and the dfw genes and provide a model system to study nonsyndromic hearing loss in mice [1].
• PMCA2 is localized to rod bipolar cells, horizontal cells, amacrine cells, and ganglion cells, and PMCA3 is predominantly expressed in spiking neurons, including both amacrine and ganglion cells but is also found in horizontal cells [2].
• Our previous studies raised the possibility that a decrease in the levels of plasma membrane calcium ATPase isoform 2 (PMCA2), a major pump extruding calcium from neurons, promotes neuronal pathology in the spinal cord during experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and after spinal cord trauma [3].
• PMCA2-null mice grow more slowly than heterozygous and wild-type mice and exhibit an unsteady gait and difficulties in maintaining balance [4].
• We report that plasma membrane calcium ATPase 2 (PMCA2) transcript and protein levels return to control values during recovery from acute disease in the Lewis rat, whereas they are reduced throughout the course of chronic, non-remitting EAE in the C57Bl/6 mouse [5].

High impact information on Atp2b2

• These mutations affecting Atp2b2 in dfw and dfw2J are the first to be found in a mammalian plasma membrane calcium pump and define a new class of deafness genes that directly affect hair-cell physiology [6].
• In the cochlea, the protein Atp2b2 is localized to stereocilia and the basolateral wall of hair cells in wild-type mice, but is not detected in dfw2J mice [6].
• Ca(2+) enters the stereocilia of hair cells through mechanoelectrical transduction channels opened by the deflection of the hair bundle and is exported back to endolymph by an unusual splicing isoform (w/a) of plasma-membrane calcium-pump isoform 2 (PMCA2) [7].
• The family also was screened for mutations in cadherin 23, which accentuated hearing loss in a previously described human family with a PMCA2 mutation [7].
• At variance with the other PMCA2 isoforms, it became activated only marginally when exposed to a Ca(2+) pulse [7].

Biological context of Atp2b2

• To examine the physiological role of PMCA2bw in lactation we compared lactating PMCA2-null mice to heterozygous and wild-type mice [8].
• 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 [4].
• In contrast, lactose was higher in milk from PMCA2-null mice during early lactation, but by day 12 of lactation there were no differences in milk lactose between the three genotypes [8].
• Since PMCA2 is expressed in the cerebellum and plays an important role to maintain the homeostasis of the intracellular Ca2+ as a Ca2+ pump, the behavioral defect can be ascribed to the impairment of Ca2+ regulation in neurons of the cerebellum [9].
• The 'Wriggle Mouse Sagami (WMS)' is a new neurological mutant with severe dystonic movements of the trunk and extremities whose pathological characters are transmitted by an autosomal recessive gene (wri) [10].

Anatomical context of Atp2b2

• Our findings suggest that a reduction in PMCA2 level or activity leading to delays in calcium clearance may cause neuronal damage and loss in the spinal cord [3].
• Importantly, the number of spinal cord motor neurons is significantly decreased in PMCA2-deficient mice and the deafwaddler(2J), a mouse with a functionally null mutation in the PMCA2 gene [3].
• A unique role in hearing is indicated by the high levels of PMCA2 expression in cochlear outer hair cells and spiral ganglion cells [4].
• 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 [4].
• 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 [4].

Associations of Atp2b2 with chemical compounds

• In this region, nucleotide transition of the plasma membrane Ca2+-ATPase isoform 2 (PMCA2) gene was found, which caused a glutamic acid to change into lysine [9].
• We now report that the levels of metabotropic glutamate receptor 1 (mGluR1), which plays essential roles in motor coordination, synaptic plasticity, and associative learning, are reduced in the cerebellum of PMCA2-null mice as compared to wild type littermates [11].

Physical interactions of Atp2b2

• Here we describe the identification and characterization of a new allele of deaf waddler (dfw2J) and present evidence for a hearing susceptibility locus (mdfw) that interacts with dfw [1].

Other interactions of Atp2b2

• The deaf waddler (dfw) mutation is a model system to study the biology of neuroepithelial hearing defects in mice [1].
• These results demonstrate that hearing loss and ataxia are dependent on gene dosage and PMCA2 dysfunction [12].
• The auditory and vestibular systems rely on the plasma membrane calcium ATPase, isoform 2 (PMCA2) to extrude calcium that enters the stereocilia during transduction [12].

Analytical, diagnostic and therapeutic context of Atp2b2

• To analyze the physiological role of PMCA2 we used gene targeting to produce PMCA2-deficient mice [4].
• First, using immunocytochemistry, we demonstrated that PMCA2 is present in control mice inner and outer hair cell stereocilia where it could pump calcium into the endolymph and that PMCA2 is absent in dfw2J stereocilia [13].

References