Intermediate lobe peptide

Melatonin [73-31-4] C 2H N202 (31) has marked effects on circadian rhythm (11). Novel ligands for melatonin receptors such as (32) (12), C2yH2gN202, have affinities in the range of 10 Af, and have potential use as therapeutic agents in the treatment of the sleep disorders associated with jet lag. Such agents may also be usehil in the treatment of seasonal affective disorder (SAD), the depression associated with the winter months. Histamine (see Histamine and histamine antagonists), adenosine (see Nucleic acids), and neuropeptides such as corticotropin-like intermediate lobe peptide (CLIP) and vasoactive intestinal polypeptide (VIP) have also been reported to have sedative—hypnotic activities (7). 

CLIP Corticotropin-hke intermediate lobe peptide OHSD Hydroxysteroid dehydrogenase PNMT Phenylethanolamine-W-methyltransferase ... 

Figure 42-15. Products of pro-opiomelanocortin (POMQ cleavage. (MSH, melanocyte-stimulating hormone CLIP, corticotropin-like intermediate lobe peptide LPH, lipotropin.)...

FIGURE 18-7 Processing of the proopiomelanocortin (POMC) precursor proceeds in an ordered, stepwise fashion. Cleavage of the POMC precursor occurs at seven sites, with some of the reactions being tissue-specific. The circled numbers indicate the temporal order of cleavage in tissues where these proteolytic events occur. ACTH, adrenocorticotropic hormone CLIP, corticotropin-like intermediate lobe peptide JP, joining peptide LPH, lipotropin MSH, melanocyte-stimulating hormone PC, prohormone convertase. 

CLIP, corticotropin-like intermediate lobe peptide. 

In addition to the weU-defined opioid systems in the central nervous system, the three opioid peptides and their precursor mRNA have also been identified in peripheral tissues. ( -Endorphin is most abundant in the pituitary, where it exists in corticotroph cells with ACTH in the anterior lobe and in melanotroph cells with MSH in the intermediate lobe (59). Enkephalin and pre-pro-enkephalin mRNA have been identified in the adrenal medulla (60) and this has been the source of material for many studies of pro-enkephalin synthesis and regulation. Pre-pro-enkephalin mRNA has also been identified in the anterior and posterior lobes of the pituitary (61). mRNA for all three opioid precursors has been identified in the reproductive system (62—64). POMC... 

Dopaminergic neurons synapse upon the parenchymal cells of the intermediate lobe (IL) of the rat pituitary gland. Dopamine decreases the capacity of the IL cells to synthesize cyclic AMP and inhibits the release of otMSH and other peptides from this tissue. The presence of a D-2 receptor accounts for both of these phenomena. This D-2 dopamine receptor can be studied in a binding assay using [3H]-spiroperidol, a dopamine... 

The above-described data show that CRF added to cells of the rat Intermediate lobe In culture causes a rapid stimulation of oe-MSH release and cyclic AMP accumulation, thus demonstrating a direct action of the peptide on pars intermedia cells (15). It is however difficult, using intact cells, to dissociate between increases in cyclic AMP levels due to stimulation of adenylate cyclase activity or to Inhibition of cyclic nucleotide phosphodiesterase or to a combination of both effects. Definitive proof of the role of adenylate cyclase In the action of CRF In the intermediate lobe of the pituitary gland is provided by the following findings of a CRF-lnduced stimulation of adenylate cyclase activity in homogenate of rat and bovine pars Intermedia cells. 

The POMC protein is processed differently in the anterior lobe than in the intermediate lobe. The intermediate lobe is rudimentary in adult humans, but is active in human fetuses, pregnant women during late gestation and in many animal species. Processing of POMC protein in peripheral tissues resembles that in intermediate lobe. There are three basic peptide groups in the POMC polypeptide (1)... 

Additional modifications of POMC peptide family There are extensive additional modifications of these peptides. Much of the N-terminal peptides of POMC as well as ACTH are glycosylated in the anterior pituitary. a-MSH is found predominantly in an N-acetylated and carboxy terminal amidated form. /3-Endorphin is rapidly acetylated in the intermediate lobe and made less active. In the hypothalamus /3-endorphin is not acetylated and is presumably active. /8-Endorphin is also trimmed in the intermediate lobe at the C-terminal end to form a- and y-endorphin. The large N-terminal fragment is also extensively cleaved but not much is known about this fragment. 

Many biologically active secreted peptides are also amidated at their carboxyl terminal, and acetylated at their amino-terminal. The consequences of these modifications are (a) to reduce the susceptibility of these peptides to degradative actions of extracellular aminopeptidases and carboxypeptidases after their secretion and (b) to influence the biological activity of the peptides. Corticotropin-releasing factor, gastrin, cholecystokinin and vasopressin require the C-terminal amide for full activity [54—56]. Acetylation of the N-terminus of a-MSH is necessary for activity, whereas acetylation of /3-endorphin inhibits its opioid activity [57], The enzymes responsible for acetylation have been identified from bovine and rat intermediate lobes [57] and enzymes with a-amidation activity have been reported in preparations of pituitary secretory granules [54,55]. 

The direct actions of DA on pituitary hormone secretion are largely inhibitory, maintaining basal secretion of prolactin from anterior pituitary lactotrophs and POMC-derived peptide hormones from intermediate lobe melanotrophs via inhibitory D2 receptors located on these cells. Episodic surges of these hormones are associated with... 

Smelik PG, Berkenbosch F, Vermes I, Tilders FJH (1983) The role of catecholamines in the control of the secretion of pro-opiocortin-derived peptides from the anterior and intermediate lobes and its implications in the response to stress. In Bhatnagar AS (Ed), The Anterior Pituitary Gland, pp. 113-125. Raven Press, New York. 

MSHs consist of three peptide hormones a-MSH, 3-MSH, and y-MSH, which are secreted by intermediate lobe of the pituitary gland. They are cleaved from the same precursor peptide as ACTH. Their basic function is stimulation of melanocytes to darken skin and stimulation of melanin synthesis to darken the skin and hair. They also have been found to be released in the brain affecting appetite, sexual arousal, and many other functions. 

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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