Studies on calcium-sensitive regulators of signal transduction in central nervous system.

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Calcium-binding proteins transduce the calcium messages into a variety of physiological responses. We have isolated a novel 23 kDa calcium-binding protein from rat brain. Based on the partial amino acid sequences, we have isolated several different clones from rat brain cDNA library, suggesting that multiple isoproteins are exist in the brain and form a new family of calcium-sensitive regulator. One of these clones was found to encode a calcium-binding protein with three EF-hand structures, consisting of 193 amino acid residues. In adult rat brain, this protein was expressed exclusively in the pyramidal cells of the hippocampus and was designated hippocalcin. Hippocalcin associates the plasma membrane in a calcium-dependent manner. Hippocalcin is myristoylated at its amino-terminal glycine residue, a key event in terms of its membrane-association property. These results suggest the involvement of hippocalcin in postsynaptic neural function. In developing rat brain, hippocalcin expression in the hippocampus increases with age, whereas the expression in the cerebral cortex and cerebellum is higher in early postnatal ages than in older ages, suggesting that the expression of hippocalcin is strictly controlled by both cell type and developmental process and that hippocalcin plays a role in neuronal differentiation in early stages of development.Isolation of the cDNA for human hippocalcin should be useful to investigate the function and expression of this protein in human brain and the possible relationship of this protein to neurological disorders. We have screened a human hipplcampus cDNA library using rat hippocalcin cDNA as a probe and obtained five different clones. One of these clones was found to encode human hippocalcin. Comparison of the human hippocalcin sequence with the corresponding rat sequence revealed an amino acid identity of 100% and nucleotide identity of 92%. The human hippocalcin gene was mapped to chromosome 1.