Prolactin receptor activation

Mechanism of prolactin receptor activation. Activation of prolactin receptor consists of ligand-induced sequential receptor homodimerization driven by the two binding sites of prolactin. In the intracellular domain of the homodimer of the ligand-receptor complex, a tyrosine kinase [known as Janus kinase 2 (Jak-2)] is activated. Jak-2 kinase causes autophosphorylation and phosphorylation of the receptor. [Reproduced with permi,ssion from M. E. Freeman,... 

Jones, M. K., W. P. Weisenburger, I. G. Sipes, and D. H. Russell. 1987. Circadian alterations in prolactin, corticosterone, and thyroid hormone levels and down-regulation of prolactin receptor activity by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Toxicology and Applied Pharmacology 87 337-350. 

The prolactin receptor, PER, which regulates milk production in mammals, belongs to the same receptor class as the growth hormone receptor. In addition to binding the hormone prolactin, PER also binds and is activated by growth hormone. The extracellular domain of PER forms a very stable 1 1 complex with growth hormone in solution this complex has been crystallized and its structure determined (Figure 13.21). We shall compare this structure with the 1 2 complex of the same hormone with GHR. 

Low-dose dopamine is not without adverse reactions and most studies have failed to evaluate its potential toxicities. Adverse reactions that may be associated with low-dose dopamine include tachycardia, arrhythmias, myocardial ischemia, depressed respiratory drive, and gut ischemia. Low-dose dopamine has also been postulated to impair resistance to infection through a reduction in prolactin concentrations.21 Furthermore, significant overlap in receptor activation occurs. Therefore, doses considered to activate only dopamine receptors may increase cardiac output and blood pressure through dopamine s effect on 3- or a-adrenergic receptors. 

Fig. 3A, B Neuropeptide effects on anxiety-related behavioiu. A The oxytocin receptor antagonist (black bars) administered intracerebroventricularly (i.c.v.) increased indices of anxiety-related behaviour in pregnant rats as measured on the elevated plus maze. Entries into the closed arms indicate unchanged locomotor activity. B Prolactin is an anxiolytic neuropeptide in female rats as revealed by i.c.v. administration of synthetic prolactin (grey and black bars represent two different doses) and by antisense targeting of the prolactin receptor (R). Vehicle (white bars) vs mixed bases (grey bars) and antisense oligodeoxynu-cleotide (black bars). p<0.05 vs vehicle (white bars). (Adapted from Nemnann et al. 2000) and Torner et al. 2001)...

Hexane extract, in Ghinese hamster ovary cells overexpressing the prolactin receptor at a concentration of 30 pg/mL, was active . 

The lipidosterolic extract, in Chinese hamster ovary cells, reduced the basal activity of a K channel and of protein kinase (PK) C. Pretreatment of the cells with the extract for 6-36 hours abolished the effects of prolactin on Ca 3 K conductance and PKC. The results indicated that the extract can block prolactin-induced prostate growth by inhibiting several steps of prolactin receptor signal transduction . 

Chinese hamster ovary cells overexpressing the prolactin receptor, was active . Protein synthesis stimulation. Sterol fraction of the extract, in cell culture at a concentration of 25 (xg/mL, produced weak activity on CA-LNCAP. A concentration of 50 (xg/mL was active on CA-PC3 h PSA production inhibition. Ethanol (70%) extract of PC-SPES (a Chinese herb combination of chrysanthemum, dyers woad, licorice, reishi, san-qi ginseng, rabdosia, saw palmetto, and baikal skullcap), in cultured prostate cancer cell line at variable doses for 24 hours, produced a significant effect in supressing cell growth in all the cell lines h... 

The interaction of the dopamine antagonist haloperidol 5 mg orally with subanesthetic doses of ketamine has been studied in a placebo-controlled study in 20 healthy volunteers over 4 days (53). Haloperidol pretreatment reduced impairment of executive cognitive functions produced by ketamine and reduced the anxiogenic effects of ketamine. However, it failed to block the ability of ketamine to produce psychosis, perceptual changes, negative symptoms, or euphoria, and it increased the sedative and prolactin responses to ketamine. These results imply that ketamine may impair executive cognitive functions via dopamine receptor activation in the frontal cortex, but that the psychoactive effects of ketamine are not mediated via dopamine receptors, but rather via NMDA receptor antagonism. 

The term neuroleptic is often applied to drngs that have relatively prominent experimental and clinical evidence of antagonism of D2-dopamine-receptor activity, with substantial risk of adverse extrapyramidal nenrological effects and inaeased release of prolactin. The term atypical antipsychotic is applied to agents that are associated with snbstantially lower risks of snch extrapyramidal effects. Representative examples inclnde aripiprazole, clozapine, quetiapine, ziprasidone, and low doses of olanzapine and risperidone. 

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