First discrete autoradiographic distribution of aminopeptidase N in various structures of rat brain and spinal cord using the selective iodinated inhibitor [125I]RB 129.
The selective and potent aminopeptidase N inhibitor [125I]RB 129 has been used for the radioautographic localization of this enzyme in rat brain, spinal cord and intestine. Brain microvessels and intestine brush-border cells were shown to present a high concentration of aminopeptidase N. Moreover, a labeling of various brain structures was observed. A very high level of binding occurred in the meninges, choroid plexus, pineal gland, paraventricular nucleus and pituitary gland. Moderate to high labeling was also observed in the cortex, caudate-putamen, subthalamic nucleus, central periaqueductal gray, thalamus, as well as in the dorsal and ventral horn of the spinal cord, which are known to contain a high concentration of enkephalins, opioid receptors and neutral endopeptidase. This co-localization confirms the physiological implication of aminopeptidase N in the inactivation of enkephalins accounting for the requirement of dual inhibition of neutral endopeptidase and aminopeptidase N to observe highly significant morphine-like effects induced by the protected endogenous opioid peptides. Aminopeptidase N was also visualized in moderate to high levels in other brain structures such as the hippocampus, nucleus accumbens, substantia nigra, hypothalamus (dorsomedial and ventromedial nuclei), raphe nucleus, pontine nucleus, inferior olive, and in high concentration in the granular layer of cerebellum. In summary, aminopeptidase N has been visualized for the first time in numerous brain areas using the selective inhibitor [125I]RB 129. This iodinated probe could allow the ex vivo and in vivo localization of aminopeptidase N in various tissues to be investigated and may also be used to evaluate quantitative changes in aminopeptidase N expression in pathological situations. Aminopeptidase N, which preferably removes NH2-terminal neutral amino acids from peptides, has probably a host of substrates. Nevertheless, a certain in vivo selectivity could be achieved by the presence of the enzyme in structures where the peptide effector and its receptors are also co-localized.
Noble
F
F
Département de Pharmacochimie Moléculaire et Structurale, INSERM U266, CNRS UMR 8600, UFR des Sciences Pharmaceutiques et Biologiques, Paris, France.
Banisadr
G
G
Jardinaud
F
F
Popovici
T
T
Lai-Kuen
R
R
Chen
H
H
Bischoff
L
L
Parsadaniantz
S M
SM
Fournie-Zaluski
M C
MC
Roques
B P
BP
D000818:Animals; D001345:Autoradiography; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001808:Blood Vessels / Q000166:cytology / Q000201:enzymology; D001921:Brain / Q000166:cytology / Q000201:enzymology*; D018826:CD13 Antigens / Q000378:metabolism*; D004027:Diencephalon / Q000166:cytology / Q000201:enzymology; D007413:Intestinal Mucosa / Q000166:cytology / Q000201:enzymology; D007457:Iodine Radioisotopes / Q000378:metabolism; D008297:Male; D008636:Mesencephalon / Q000166:cytology / Q000201:enzymology; D020540:Metencephalon / Q000166:cytology / Q000201:enzymology; D007470:Monoiodotyrosine / Q000031:analogs & derivatives* / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000201:enzymology*; D009830:Olfactory Bulb / Q000166:cytology / Q000201:enzymology; D010870:Pineal Gland / Q000166:cytology / Q000201:enzymology; D010902:Pituitary Gland / Q000166:cytology / Q000201:enzymology; D011480:Protease Inhibitors / Q000378:metabolism*; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D013116:Spinal Cord / Q000166:cytology / Q000201:enzymology*; D013687:Telencephalon / Q000166:cytology / Q000201:enzymology
C404566:2(S)-benzyl-3-hydroxy(1'(R)-aminoethyl)phosphinylpropanoyl-L-3-iodotyrosine; D007457:Iodine Radioisotopes; D011480:Protease Inhibitors; D018826:CD13 Antigens; D007470:Monoiodotyrosine