TRANSCRIPT DISTRIBUTION OF PLASMA-MEMBRANE CA2+ PUMP ISOFORMS AND SPLICE VARIANTS IN THE HUMAN BRAIN

Plasma membrane calcium pumps (PMCAs) play a major role in the mainten ance and fine regulation of the intracellular Ca2+ concentration. Four teen subregions of the normal human brain were carefully dissected and analyzed by reverse transcriptase-polymerase chain reaction for the d istribution of mRNAs corresponding to the four known PMCA genes as wel l as their alternative splicing products at two previously defined 'ho tspots' A and C. All PMCA genes were found to be expressed in every br ain subregion; however, consistent differences were found in the distr ibution of alternative splice options. The four cortical regions and h ippocampus were characterized by the relative preference of variants t hat include an entire exon at site C and lead to the expression of iso forms of the a-type. Inferior olive and olfactory bulb showed a relati ve preponderance of the b-form 'default' types of alternative splicing at site C, and a decrease or even the lack of 'differentiated' forms such as variants la and 1c. At the N-terminal splice site A, the defau lt x-type variants were predominant in all brain regions for PMCA 1, 3 , and 4. By contrast, the pattern of PMCA2 variants was the most varia ble, ranging from the presence of the entire set of 2x, 2w, and 2z for ms in inferior olive to the almost exclusive presence of form 2z (excl uding all alternatively spliced sequences) in the four cortical region s, caudate, and hippocampus. Regional differences in the PMCA splice t ype distribution in normal human brain may correlate with different de mands on the regulation of the set-point resting Ca2+ levels in these areas. Changes in these patterns may correlate with altered physiologi cal states of the affected regions and/or reflect an (early) sign of C a2+ dyshomeostasis characteristic of many neurodegenerative diseases.