BRAIN SPECIFIC PROTEINS AND NERVE FUNCTION

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The family of membrane Ca2+-pumping ATPases are essential for maintaining resting state levels of cytosolic free Ca2+-ATPases which are distinct from those of internal membranes in structure, function, and regulatory properties and in physiological roles. As set forth in the PROGRESS REPORT and SIGNIFICANCE sections, substantial progress has been made in the studies of the plasma membrane Ca2+ pump in animal cells and it's regulation. The structures of nine distinct isoforms of the enzyme have been deduced from studies of their respective cDNAs. Based on their primary structures, these isoforms are products of differential splicing of primary transcripts of at least four distinct genes. While the regions of the molecule which form the core enzyme appear to be largely conserved in all isoforms, the C-terminus of the molecule responsible for regulation of activity differs substantially among different isoforms. This provides the basis for differential regulation of activity to meet the needs of different physiological settings. Elucidation of the regulatory properties of individual isoforms and the regulation of their expression during development and in response to cellular perturbation is essential for gaining a complete understanding of Ca2+-dependent regulation in animal cells. Studies in this application will focus primarily on the isoform which we initially cloned from bovine and human cDNA libraries and the isoforms most closely related to it, including one of the major isoforms of the human erythrocyte. A variety of approaches will be used to study the molecular mechanisms governing the regulation of activity through calmodulin and reversible phosphorylation, to determine the relative importance of these regulatory processes in vivo, and to examine the regulation of expression of this and other isoforms under a variety of physiological conditions.