Disease relevance of ATP2B2

• Recently, a variant of the human ATP2B2 gene was shown to exacerbate hearing loss in individuals homozygous for a CDH23 mutation, similar to the Atp2b2(dfw-2J)-Cdh23(753A/G) interaction affecting hearing in mice [1].
• We also detected PMCA2 mRNA expression in all the breast cancer cell lines examined [2].
• Full-length cDNAs for the three human plasma membrane Ca2+ pump isoforms 2 (PMCA2) differently spliced at the A site were constructed and transferred to baculovirus [3].
• The PMCA2 gene is contained within this region and deletion of this gene may cause congenital heart defects [4].

High impact information on ATP2B2

• In organotypic cultures, Ca(2+) imaging of vestibular hair cells showed that the dissipation of stereociliary Ca(2+) transients induced by Ca(2+) uncaging was compromised in the dfw and PMCA2 knockout mice, as was the sensitivity of the mechanoelectrical transduction channels to hair bundle displacement in cochlear hair cells [5].
• The family also was screened for mutations in cadherin 23, which accentuated hearing loss in a previously described human family with a PMCA2 mutation [5].
• At variance with the other PMCA2 isoforms, it became activated only marginally when exposed to a Ca(2+) pulse [5].
• A deafness-inducing missense mutation of PMCA2 (G293S) has been identified in a human family [5].
• 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) [5].

Biological context of ATP2B2

• Localization of two genes encoding plasma membrane Ca2+ ATPases isoforms 2 (ATP2B2) and 3 (ATP2B3) to human chromosomes 3p26-->p25 and Xq28, respectively [6].
• The splicing complexity at site C was found to be augmented in the transcripts of PMCA2 and PMCA3 through the use of additional exons, and in PMCA1 and 3 through the use of additional internal splice sites in the single alternatively spliced 154-base pair exon [7].
• Instead, we found that alternative splicing affecting the first cytosolic loop determined apical membrane targeting of PMCA2 [8].
• PMCA2 in particular is upregulated extensively during lactation [9].
• A 1.2-Mb bacterial-artificial-chromosome (BAC)/P1 contig was constructed, bounded by the marker D3S3691 distally and by the gene ATP2B2 proximally [10].

Anatomical context of ATP2B2

• The PMCA2 and PMCA3 proteins were only found in neuronal tissues; the PMCA2 protein was present in high concentrations in the cerebellum and in the cerebral cortex [11].
• PMCA2 gene was expressed at low levels in adult heart but was not detected in fetal heart [12].
• These data report the first differential effect of alternative splicing within the first cytosolic loop of PMCA2 and help explain the selective enrichment of specific PMCA2 isoforms in specialized membrane compartments such as stereocilia of auditory hair cells [8].
• To explore whether PMCA2 and PMCA4 expression may be deregulated in breast cancer, we compared mRNA expression of these PMCA isoforms in tumorigenic and non-tumorigenic human breast epithelial cell lines using real time RT-PCR [9].
• PMCA2 was found in liver, adrenal gland, spinal cord, and brain [13].

Associations of ATP2B2 with chemical compounds

• These data imply that cerebellar neurons possess remarkably effective mechanisms to target and restrict PMCA2 and -3 to specific membrane domains, raising the possibility that calcium pumps contribute to local Ca(2+) signaling [14].

Physical interactions of ATP2B2

• We have isolated and ordered yeast artificial chromosomes (YACs) and cosmids surrounding the von Hippel-Lindau (VHL) tumor suppressor and plasma membrane Ca(2+)-transporting ATPase isoform 2 (PMCA-2) genes on chromosome 3p25-26 [15].

Other interactions of ATP2B2

• PMCA1 and PMCA2 were found mainly on basal and wing cells [16].
• Although differences in PMCA4 mRNA levels were observed between breast cell lines, they were not of the magnitude observed for PMCA2 [9].
• Immunohistochemistry revealed that CaT-Like is located in the basolateral plasma membrane of acinar cells; while calbindin-2, SERCA-2 and SERCA-3 were found inside the acinar cells; and PMCA-2 was found in the apical membrane and in the secretory canaliculi between the cells [17].
• A fourth syntenic marker (ATP2B2), at a more distal human SRO (3p26-->p25), indicated that human 3pter-->p14 is evolutionarily conserved in Ateles chromosome 3 (APC 3) [18].
• This physical map of the cloned region will allow a detailed analysis of both the PMCA-2 and VHL genes [15].

Analytical, diagnostic and therapeutic context of ATP2B2

• Protein bands at approximately 130, 115, and 135kDa were detected by Western blot analysis for PMCA1, PMCA2 and PMCA4, respectively [19].

References