V

Common to all species

Species differ-immunological specificity

FIGURE 5-11 Linear sequence of human ACTH. Arrows point to hydrolytic cleavage and residual activity is denoted in boxes as a percentage of activity of the native structure after cleavage at a specific linkage. a-MSH comprises the first 13 amino acid sequence from the N-terminus. fi-Cell tropin has the same sequence as ACTH22-39. Immunological specificity is conferred by sequence 25-33, and the invariable C-terminal sequence is 34-39. CLIP: corticotropin-like intermediary peptide. These data are a summary from a number of different literature sources.

rect precursor of the ancestral gene for both PRL and GH. The human GH gene family contains GH and four placental genes: GH variant and CSA, CSB, and CSL. PRL is a single human gene. The situation of PRL-like genes in the rodent is very complex, and since this complexity is not reflected in the human, the rodent picture will not be discussed. High-molecular-weight forms of CS protein exist in the human and may be explained by the formation of heterodimers of CS and a2-macroglobulin. So far, there is no evidence for the existence of PRL in such forms.

Because a subset of lactrotrophs secretes both PRL and GH, it appears that the common transcription factor activating both genes may be Pit-1. Two similar sequences of the GH and the PRL promoters contain the AT-rich moiety A(T / A)(T / A)TATNCAT. Details of the human prolactin gene and processing to mRNA and protein, as well as the promoter region of the rat PRL gene, are shown in Figure 5-16A.

The most obvious role of prolactin is in the differentiation of the mammary gland cells and as a signal in the differentiated cells to produce milk proteins and other constituents. Prolactin may act like a secondary growth hormone, particularly on the liver. PRL also can act on the testis to stimulate the production of testosterone. It seems to have some role in stress adaptation as its release from the anterior pituitary is signaled by the release of /3-endorphin in response to stress and as a consequence of the action of CRH; (3-endorphin then acts, apparently directly, on the mam-motrope (lactotrope) to stimulate the release of PRL. It has been known for some time that nursing an infant on demand over a long period of time creates a period in which pregnancy rarely occurs. This is apparently the result of frequent release of PRL from the anterior pituitary in response to suckling, which may have the effect of reducing GnRH release from the hypothalamus.

Prolactin derives from the lactotroph of the anterior pituitary. These cells represent about 20% of pituitary cells, and this proportion is similar in males and females, suggesting a significant role for PRL in the male. PRL receptors occur in the Leydig cells of the testis and other sexual tissues. It appears that PRL maintains the level of LH receptors, which, in turn, facilitates the action of LH and maintains levels of testosterone production. There are other activities of PRL in the male. Lactotrophs synthesize PRL exclusively, but there is a minority of cells that can synthesize and secrete both PRL and GH. A DNA-binding protein named Pit-1 has been characterized that appears to activate the PRL gene. A similar factor called GHF-1 carries out an analogous function in stimulating the production of GH, and the two factors are probably identical. Knockout of the Pit-1 function decreases the expression of PRL and GH and diminishes growth in cell culture experiments. The Pit-1 message is expressed in somatotrophs, lactotrophs, and thyrotrophs. Pit-1, after transfection, will activate PRL gene expression. It is apparent that other cell-specific nuclear factors are required to generate a specific hormonal response. Like several other transcriptional activators, Pit-1 is most efficient in stimulating PRL expression when two molecules of Pit-1 interact at the DNA level. Mutations in the Pit-1 gene have been found in certain genetic strains of dwarf mice, suggesting that Pit-1

FIGURE 5-12 Structural relationship of -y-LPH, /3-MSH, Met-enkephalin, and /3-endorphin to the ovine /3-LPH structure. Reproduced from Li, C. H. (1982). "Biochemical Actions of Hormones" (G. Litwack, ed.), Vol. 9, pp. 1-41. Academic Press, NY.

function is required for the elaboration of GH (and PRL), and presumably this will have significance for human dwarfism.

Estrogen is known to stimulate the production of PRL. It is likely that the estrogen receptor interacts with Pit-1 since cotransfection of estrogen receptor and Pit-1 results in the stimulation of PRL transcription, whereas transfection of the estrogen receptor alone, in an estrogen receptor-deficient cell line, does not enhance PRL expression. Glucocorticoids, on the other hand, negatively affect the PRL promoter.

A. Regulation of Prolactin Release

There is a discussion of the regulation of PRL release in Chapter 14. Significant positive regulators include estrogen, VIP, and TRH, and the negative regulator is dopamine. A summary of the signal transduction processes for these effectors is shown in Figure 5-17.

PIF, the endogenous inhibitor of PRL release, appears to be dopamine. If dopamine receptor function is blocked by a drug, such as phenothiazine or metoclopramide, a rise in PRL occurs. Dopamine (DA), from the dorsomedial area of the arcuate nucleus and the inferior ventromedial nucleus of the hypothalamus, is released into the median eminence, where DA-carrying axon terminals represent one-third of all the axon terminals in the zona externa of the median eminence. This is the tuberoinfundibular dopamine (TIDA) pathway. Certain TIDA axons project into the posterior and intermediate lobes of the pituitary. TI dopamine binds to D2 dopamine receptors on the lactotroph, resulting in decreased adenyl-

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