Study on Physiological Roles of Neuropeptidases

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The physiological action of neuropeptides at the synape is terminated through enzymatic degradation by membrane-bound proteases. We have defined, purified, and characterized membrane-bound proteases functioning in degradation of four neuropeptides, substance P, LHRH (luteinizing hormone-releasing hormone), dynorphin, and somatostatin. 1. We have analyzed the degradation of substance P by neuronal cells cultured from rat fetal brain and found that a metallo-endopeptidase showing properties almost identical with those of the substance P-degrading enzyme purified from rat brain by us is involved in the degradation likely as the degradation by neuroblastoma cells and rat synaptic membrane. On the other hand, it was found that endopeptidase-24.11 functions in the degradation by glioma cells and glial cells cultured from rat fetal brain. The latter enzyme has been purified from glioma cells. 2. LHRH fragment (1-5)-generating enzyme that plays an important role in the initial stage of LHRH-degradation haed been purified from neuroblastoma cells and rat brain synaptic membrane. The enzyme has been characterized as a metallo-endopeptidase whose sulfhydryl groups are essential for the maintenance of the activity. It was also found that similar enzymes play important roles in degradation by neuronal and glial cells cultured from rat fetal brain. 3. One of two dynorphin-degrading cysteine proteases has been characterized as a novel enzyme with highly strict specificity toward only Arg-Argbond among four kinds of paired basic residues. 4. The degradation of somatostatin in the rat hippocampal synaptic membranes was found to be initially triggerd by the action of endopeptidase-24.11.