Peptides Derived from Proopiomelanocortin POMC

Another major source of endogenous opioid peptides as well as non-opioid peptides is proopiomelanocortin (POMC). This large peptide contains the sequences of, and is processed into, a number of smaller peptides, including ACTH, P-endorphin, P-lipotropin, a-MSH, P-MSH and y-MSH. Which products are derived from POMC depends upon the cell in which the processing takes place. In the anterior lobe of the pituitary POMC is processed into ACTH and P-lipotropin. In the neurointermediate lobe the major products are P-endorphin, a-MSH and y-MSH. POMC was the first of the peptide precursors for which such cell-dependent processing was demonstrated. 

The discovery by Blalock and colleagues that POMC was also produced by immune cells was a major event in the developing recognition of interactions between the immune and nervous systems (reviewed in Blalock, 1999). These studies indicated that not only do neurohormones derived from the nervous system alter immune system activity, but also similar or identical hormones can be released from immune cells to regulate the nervous system as well as the immune system itself. 

Similar to what was found with the PENK-derived enkephalins, peptides derived from POMC frequently have biphasic dose-response curves that is, low doses stimulate immune system function whereas high doses usually suppress function. Again, it appears the system is designed to maintain homeostasis in response to a wide range of conditions. 

The finding that the immune and neuroendocrine systems both express receptors for opioids and for ACTH and that both systems can synthesize and release peptides active at these receptors, led to the suggestion that the immune system functions as a sensory organ (Blalock, 1984, 1999) and that this forms the basis for the interaction between the two systems. It is well known that the nervous system responds to a variety of stimuli and, when appropriate, releases neurotransmitters and hormones that enable an appropriate reaction to these stimuli or stresses. This can include changes in immune system function. Blalock proposed that the immune system also responds to particular stimuli, in this case environmental changes that would not be readily detected by the nervous system, such as the presence of bacteria or viruses. In response, the immune system releases a variety of compounds, including peptide hormones that will alter both immune and nervous system function. 

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The classical mammalian opioid peptides are derived from three distinct precursor proteins (Fig. 7.10) (see Refs. 75,266 for reviews). Processing of the precursor proteins occurs at pairs of basic residues. jS-Endorphin is derived from proopiomelanocortin (POMC), along with ACTH, a-MSH, and j3-lipotropin (see Ref 267 for a review). The enkephalins are derived from proenkephalin A (see Ref 268 for a review). This protein contains four copies of Met-enkephalin flanked by pairs of basic resi-... 

The classic endogenous opioid peptides are derived from one of three families of precursors proopiomelanocortin (POMC), pro-dynorphin, and pro-enkephalin. Many active opioid peptides are derived from these three, but the best known are )S-endorphin, enkephalin, and dynorphin. POMC is produced by nuclei in the hypothalamus and medulla (Khachaturian et al. 1985 Watson et al. 1978 Bloom et al. 1978). Enkephalin and dynorphin neurons are distributed to all levels of the central nervous system (Hokfelt et al. 1977 Khachaturian et al. 1983 Sar et al. 1978 Khachaturian et al. 1985). 

Fig. 1. Processing of proopiomelanocortin (POMC) the precursor for the melanocortins and opiates in the mammalian pituitary gland. Processing occurs by proteolytic cleavage at sites of paired amino acids, some of which are shown here as dark bands. In both the anterior and the intermediate lobes, POMC is processed into an ACTH biosynthetic intermediate and into )J-lipotropin ()3-LPH 1-91). In the anterior lobe, subsequent processing yields the two biologically important products, ACTH 1-39 and )S-MSH. In the intermediate lobe, ACTH 1-39 is further processed to yield a-MSH (ACTH 1-13) and corticotropin-like intermediate peptide (CLIP). -MSH is derived, via y-MSH, from the 16-K fragment of POMC. This hormone varies in length in different species. Also in the intermediate lobe, /3-LPH is processed to produce p-endorphin 1-31. Many other small peptide fragments, of uncertain biological properties, are also produced, (from Strand et al., 1989).

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