Proopiomelanocortin gene and gene products: A comparative study

Abstract

The beneficial effects of morphine, mainly euphoria and analgesia, have been known for several centuries. However, it is only twenty years ago that the story of endogenous opioid peptides started. In 1971, Goldstein and collaborators established the existence of receptors to morphine within the brain (Goldstein et al., 1971). The discovery of the numerous endogenous ligands of these receptors began in 1974 (Terenius and Wahlstrom, 1974). After these first and somewhat hesitating steps, the tale of opioids has been written extremely quickly. The main opioid peptides, beta-endorphin, Met-enkephalin, Leu-enkephalin, and the dynorphins, are today established to derive from three large precursors. Proopiomelanocortin (POMC), proenkephalin and prodynorphin were cloned and sequenced within a few years (Nakanishi et al., 1979; Noda et al., 1982; Kakidani et al., 1982). These three precursors are all large prohormones processed into several biologically active peptides, these being separated by pairs of basic amino-acid residues. Proopiomelanocortin, precursor of betaendorphin, is probably the most studied of these three molecules. It was first shown to be expressed in the pituitary, both in the corticotroph cells of the anterior lobe, where it is mainly processed into adrenocorticotropin (ACTH) and beta-lipotropin (BLPH), and in the melanotroph cells of the intermediate lobe, where it is cleaved into alphamelanocyte stimulating hormone (AMSH), corticotropin-like intermediate lobe peptide (CLIP), gamma-lipotropin (GLPH) or betamelanocyte stimulating hormone (BMSH) and beta-endorphin (BEnd). Although they were first supposed to be only expressed in nervous tissues, POMCderived peptides have been observed in many non-pituitary tissues such as the reproductive tract (Tsong et al., 1982), gastrointestinal tract, kidney, liver and heart (Saito and Odell, 1983; DeBold et al., 1988). They are also synthesized in several cells of the immune system (DiAugustine et al., 1980; Smith and Blalock, 1981; LacazeMasmonteil et al., 1987; Lolait et al., 1986) and constitute for this reason important common signal molecules of the neuroendocrine and the immune systems.