The recent isolation and identification of a-N-acetyl forms of the C-Fragment of lipotropin (fl-endorphin, residues 61-91) and the C'-Fragment (residues 61-87) [Smyth, D. G., Massey, D. E., Zakarian, S. & Finnie, M. (1979) Nature (London) 279, 252-254] has led to a study of their distribution in the pituitary and brain of the rat. Regions were mapped by the method of immunofluorescent staining and the reactive peptides were determined by immunoassay after extraction, gel filtration, and ion exchange chromatography. The major immunoreactive peptides in both lobes of the pituitary were found to be C'-Fragment and N-acetyl C'-Fragment, which are weakly active or inactive as opiates; the C-Fragment and its N-acetyl derivative represented minor components. This indicates that in the rat the circulating "endorphins" released from pituitary would have little morphinomimetic activity. The same four immunoreactive peptides were observed in rat brain. In the hippocampus the C'-Fragment was the principal component; in the midbrain there was more C-Fragment but C'-Fragment predominated; in the hypothalamus the C-Fragment was the major peptide, almost to the exclusion of the other peptides. The results demonstrate that the processing of lipotropin is under differential control in anatomically distinct regions of the central nervous system. The processing of lipotropin in the hypothalamus is directed specifically to the production of lipotropin C-Fragment.Understanding of the full physiological role of the endorphins must start from the identification of these peptides and elucidation of their distribution in regions of pituitary and brain. Present in picomolar concentrations, they can be detected and measured by the application of highly sensitive immunological techniques involving the use of specific antibodies. In studies of f3-endorphin [lipotropin (LPH) C-Fragment] the antisera employed have exhibited COOH-terminal specificity (1-4) and would react with the a-N-acetyl derivatives of the C-and C'-Fragments of LPH, as well as with a series of peptides including the 31,000-Mr endorphin prohormone, LPH, the C-Fragment (residues , and the C'-Fragment (residues 61-87). All these peptides occur naturally, but previous studies on the distribution of ,B-endorphin by immunofluorescence (5, 6) or by radioimmunoassay of tissue extracts after gel filtration (7-10) have not differentiated between them. Because only the CFragment exhibits potent opiate activity-the C'-Fragment is '/5ooth as active as an analgesic agent (11) and the acetyl peptides (12) and LPH (13,14) are inert-it is essential that the immunoreactive peptides should be precisely identified. We give here a brief description of our detailed mapping of the pituitary and brain of the rat by immunofluorescence using antibodies raised against homogeneous porcine C-Fragment and we present the results of experiments that have allowed characterization of the fluorescing substances in specific regions. The data reveal strikingly different patterns of distribution of ...
beta-Endorphin, the most potent known naturally occurring analgesic agent, is found in pituitary and brain in company with a series of structurally and biosynthetically related peptides that are essentially devoid of opiate activity. In studies of beta-endorphin it is important to discriminate between the active and inactive forms of the peptide. This review describes the use of chemical and immunological methods for localizing the peptides in the tissues, extracting and resolving the peptides by chromatography, and determining the concentrations of the peptides by radioimmunoassay. These approaches have allowed the distribution of beta-endorphin and its related peptides to be assigned unequivocally in regions of rat pituitary and brain. It has been found that the multifunctional corticotropin-endorphin prohormone can undergo processing by different mechanisms in different tissues, permitting the intrinsic activities of its fragments to be expressed selectively. The different processing patterns can be attributed to the existence of highly specific enzymes, characteristic of individual cells, which regulate the formation of this potent opiate.
The prohormone of beta-endorphin is unusual in that it is the precursor of more than one biologically active peptide (Fig. 1). The activation of this prohormone, to produce corticotropin (ACTH), alpha-melanotropin (alpha-MSH) and beta-endorphin, would seem to be relatively complex as its processing pattern is known to differ between tissues. Thus ACTH is produced in the anterior pituitary whereas alpha-MSH is formed in the pars intermedia; similarly, lipotropin and beta-endorphin seem to predominate in the anterior pituitary whereas beta-endorphin alone has been thought to be the principal component in the pars intermedia. We report here a study of the distribution of beta-endorphin-related peptides in various regions of porcine pituitary. The main products in the anterior pituitary were lipotropin and the potent analgesic form of beta-endorphin, whereas the main products in the pars intermedia were the inactive lipotropin C'-fragment and its N-acetyl derivative. Thus the processing of the C-terminal region of the beta-endorphin prohormone differs markedly between the two regions of porcine pituitary.
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