Comparative fine structural distribution of endopeptidase 24.15 (EC3.4.24.15) and 24.16 (EC3.4.24.16) in rat brain

Endopeptidase 24.15 (EP24.15) and 24.16 (EP24.16) are closely related metal loendopeptidases implicated in the metabolism of several neuropeptides and widely expressed in mammalian brain. To gain insight into the functional ro le of these two enzymes in the central nervous system, we examined their ce llular and subcellular distribution in rat brain by using electron microsco pic immunogold labeling. In all areas examined, EP24.15 and EP24.16 immunor eactivity were observed in selective subpopulations of neuronal and glial c ells. Subcellular localization of EP24.15 in neurons revealed that this enz yme was predominantly concentrated in the nucleus, whereas EP24.16 was almo st exclusively cytoplasmic. The amount of EP24.15 found in the nucleus was inversely correlated with that found in the cytoplasm, suggesting that the enzyme could be mobilized from one compartment to the other. Within the cyt oplasm, EP24.15 and EP24.16 immunoreactivity showed comparable distribution al patterns. Both enzymes were detected throughout perikarya and dendrites, as well as within axons and axon terminals. In all neuronal compartments, EP24.15 and EP24.16 showed a major association with membranes of neurosecre tory elements, including Golgi cisternae, tubulovesicular organelles, synap tic vesicles, and endosomes. However, whereas EP24.15 always faced the cyto plasmic face of the membranes, EP24.16 was observed on both cytoplasmic and luminal sides, suggesting that the latter was more likely to contribute to the processing of peptides or to the degradation of internalized ligands. Taken together, the present results suggest that EP24.15 could play a major role in the hydrolysis of intranuclear substrates, whereas EP24.16 would b e predominantly involved in the processing and inactivation of signaling pe ptides. J. Comp. Neurol. 438:399-410, 2001. (C) 2001 Wiley Liss, Inc.