Blastocyst H(2) receptor is the target for uterine histamine in implantation in the mouse.
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The process of implantation is a 'two-way' interaction between the blastocyst and uterus. It has long been suspected that histamine is an important mediator in embryo-uterine interactions during implantation, but its source, targets and mechanism of actions remained undefined. We have recently demonstrated that uterine epithelial cells are the source of histamine, which peaks on day 4 of pregnancy (the day of implantation) in the mouse. In searching for its target and site of action, we discovered that preimplantation blastocysts, which express histamine type 2 receptor (H(2)), is the target for histamine action. Using multiple approaches, we demonstrate herein that uterine-derived histamine interacts with embryonic H(2) receptors in a paracrine fashion to initiate the process of implantation. (+info)
Long-lasting cholecystokinin(2) receptor blockade after a single subcutaneous injection of YF476 or YM022.
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Histamine-forming ECL cells in the rat stomach operate under the control of gastrin. They represent a convenient target for studying cholecystokinin-B/gastrin (CCK(2)) receptor antagonists in vivo. We examined the effectiveness and duration of action of two CCK(2) antagonists, YM022 and YF476, with respect to their effect on ECL-cell histidine decarboxylase (HDC) activity in the rat. Oral administration of subcutaneous deposition of YF476 or YM022 reduced the HDC activity. The maximum/near-maximum dose for both drugs and for both modes of administration was 300 micromol kg(-1) (effects measured 24 h after dose). At this dose and time the serum concentration of YF476 was 20 - 40 nmol l(-1). The dose 300 micromol kg(-1) was used in all subsequent studies. A single subcutaneous injection of YF476 inhibited the HDC activity for 8 weeks. The circulating concentration of YF476 remained high for the same period of time (>/=15 nmol l(-1)). Subcutaneous YM022 suppressed the HDC activity for 4 weeks. A single oral dose of YF476 or YM022 inhibited the HDC activity for 2 - 3 days. Chronic gastric fistula rats were used to study the effect of subcutaneous YF476 on gastrin-stimulated acid secretion. A single injection of YF476 prevented gastrin from causing an acid response for at least 4 weeks (the longest time studied). We conclude that a single subcutaneous injection of 300 micromol kg(-1) YF476 causes blockade of CCK(2) receptors in the stomach of the rat for 8 weeks thus providing a convenient method for studies of the consequences of long-term CCK(2) receptor inhibition. (+info)
Amino- and carboxy-terminal PEST domains mediate gastrin stabilization of rat L-histidine decarboxylase isoforms.
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Control of enzymatic function by peptide hormones can occur at a number of different levels and can involve diverse pathways that regulate cleavage, intracellular trafficking, and protein degradation. Gastrin is a peptide hormone that binds to the cholecystokinin B-gastrin receptor and regulates the activity of L-histidine decarboxylase (HDC), the enzyme that produces histamine. Here we show that gastrin can increase the steady-state levels of at least six HDC isoforms without affecting HDC mRNA levels. Pulse-chase experiments indicated that HDC isoforms are rapidly degraded and that gastrin-dependent increases are due to enhanced isoform stability. Deletion analysis identified two PEST domains (PEST1 and PEST2) and an intracellular targeting domain (ER2) which regulate HDC protein expression levels. Experiments with PEST domain fusion proteins demonstrated that PEST1 and PEST2 are strong and portable degradation-promoting elements which are positively regulated by both gastrin stimulation and proteasome inhibition. A chimeric protein containing the PEST domain of ornithine decarboxylase was similarly affected, indicating that gastrin can regulate the stability of other PEST domain-containing proteins and does so independently of antizyme/antizyme inhibitor regulation. At the same time, endoplasmic reticulum localization of a fluorescent chimera containing the ER2 domain of HDC was unaltered by gastrin stimulation. We conclude that gastrin stabilization of HDC isoforms is dependent upon two transferable and sequentially unrelated PEST domains that regulate degradation. These experiments revealed a novel regulatory mechanism by which a peptide hormone such as gastrin can disrupt the degradation function of multiple PEST-domain-containing proteins. (+info)
The histidine decarboxylase (HDC) gene of Tetrahymena pyriformis is similar to the mammalian one. A study of HDC expression.
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RNA was isolated from Tetrahymena pyriformis GL and using human histidine decarboxylase (HDC) gene primers, the RT-PCR product was sequenced. A fraction containing 207 base pairs was compared to the published sequences of prokaryotic and mammalian (rat, mouse and human) HDC cDNA (exons). The HDC-cDNA fraction of Tetrahymena was similar to the mammalian cDNA-s and it was completely different from the prokaryotic HDC-gene. The results indicate the presence of a mammalian-like HDC-gene already in a unicellular eukaryote organism and demonstrates also that the divergence of the prokaryotic-eukaryotic common gene took place already at this low evolutionary level. (+info)
The mouse L-histidine decarboxylase gene: structure and transcriptional regulation by CpG methylation in the promoter region.
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To investigate the regulation of mouse L-histidine decarboxylase (HDC) gene expression, we isolated genomic DNA clones encoding HDC. Structural analysis revealed that the mouse HDC gene was composed of 12 exons, spanning approximately 24 kb. Northern blotting analysis indicated that, among the cell lines examined, a high level of HDC gene expression was restricted to mature mast cell lines and an erythroblastic cell line. The gene was induced strongly in the mouse immature mast cell line P815 after incubation in the peritoneal cavity of BDF1 mice. We observed that the promoter region was demethylated in the HDC-expressing cell lines and in induced P815 cells. Interestingly, forced demethylation by 5-azacytidine (5-azaC) treatment induced high expression of HDC mRNA in P815 cells. The activity of a mouse HDC promoter-reporter construct stably transfected in P815 cells was repressed by in vitro patch-methylation. This low promoter activity of the patch-methylated reporter construct was restored after 5-azaC treatment, which demethylated the patch-methylated promoter. These results indicate that DNA methylation state of the promoter region controls HDC gene expression. (+info)
Octreotide inhibits the enterochromaffin-like cell but not peroxisome proliferator-induced hypergastrinemia.
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The peroxisome proliferator ciprofibrate induces hypergastrinemia and as a consequence, enterochromaffin-like (ECL) cell hyperplasia. The mechanism for the gastrin cell stimulation is unknown. The somatostatin analog octreotide LAR (long-acting release) was used to see if the stimulating effects of ciprofibrate could be attenuated. Female Fischer rats were dosed with ciprofibrate (50 mg/kg body weight per day) alone or combined with octreotide LAR (10 mg/30 days) for 60 days. Plasma gastrin and histamine, gastric endocrine cell densities and mRNA abundances were measured. Ciprofibrate increased gastrin mRNA abundance (P<0.05), gastrin cell number (P<0. 001) and cell area (P<0.01), and induced hypergastrinemia (P<0.001). These rats had profound ECL cell hyperplasia, confirmed by an increase in chromogranin A (CgA) and histidine decarboxylase (HDC) mRNA, density of neuroendocrine and ECL cells and plasma histamine levels (all P<0.001). Octreotide LAR did not affect ciprofibrate stimulation of gastrin cells, but all parameters of ECL cell hyperplasia were reduced (P<0.001). Octreotide LAR also significantly inhibited basal ECL cell function and growth. Ciprofibrate stimulates gastrin cell activity by a mechanism unaffected by octreotide, but octreotide does inhibit basal and gastrin-stimulated ECL cell function and growth. (+info)
Central histamine contributed to temperature-induced polypnea in mice.
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Breathing pattern is influenced by body temperature. However, the central mechanism for changing breathing patterns is unknown. Central histamine is involved in heat loss mechanisms in behavioral studies, but little is known about its effect on breathing patterns. We examined first the effect of body temperature on breathing patterns with increasing hypercapnia in conscious mice and then that of the depletion of central histamine by S(+)-alpha-fluoromethylhistidine hydrochloride (alpha-FMH) (100 mg/kg ip), a specific inhibitor of histidine decarboxylase, at normal and raised body temperatures. A raised body temperature increased respiratory frequency with reductions in both inspiratory and expiratory time and decreased tidal volume. On the other hand, alpha-FMH lowered respiratory frequency with a prolongation of expiratory time at the raised temperature; however, this was not observed at a normal temperature. These results indicate that central histamine contributes to an increase in respiratory frequency as a result of a reduction in expiratory time when body temperature is raised. (+info)
Involvement of interleukin-1 in the inflammatory actions of aminobisphosphonates in mice.
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Aminobisphosphonates (aminoBPs) are potent inhibitors of bone resorption. However, they cause undesirable inflammatory reactions, including fever, in humans. Intraperitoneal injection of aminoBPs into mice also induces inflammatory reactions, including a prolonged elevation of the activity of the histamine-forming enzyme, histidine decarboxylase (HDC). Because interleukin-1 (IL-1) is a typical pyrogen and a strong inducer of HDC, we examined whether aminoBPs induce inflammatory reactions in mice deficient in genes for both IL-1alpha and IL-1beta (IL-1-KO mice). In control mice, aminoBPs induced an elevation of HDC activity and other inflammatory reactions (enlargement of the spleen, atrophy of the thymus, exudate in the thorax and increase in granulocytic cells in the peritoneal cavity). These responses were all weak or undetectable in IL-1-KO mice. We have previously shown that lipopolysaccharides (LPSs) from Escherichia coli and Prevotella intermedia (a prevalent gram-negative bacterium both in periodontitis and endodontal infections) are capable of inducing HDC activity in various tissues in mice. In control mice treated with an aminoBP, the LPS-induced elevations of serum IL-1 (alpha and beta) and tissue HDC activity were both markedly augmented. However, such an augmentation of HDC activity was small or undetectable in IL-1-KO mice. These results, taken together with our previous findings (i) suggest that IL-1 is involved in the aminoBP-induced inflammatory reactions and (ii) lead us to think that under some conditions, inflammatory reactions induced by gram-negative bacteria might be augmented in patients treated with an aminoBP. In this study, we also obtained a result suggesting that IL-1-deficiency might be compensated by a second, unidentified, mechanism serving to induce HDC in response to LPS when IL-1 is lacking. (+info)