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M Berelowitz

Publications and source records attributed to M Berelowitz.

At least 19 recordsLinked to original sources
PubMed1992

Molecular cloning and functional expression of a brain-specific somatostatin receptor.

The PCR and conventional library screening were used to clone the brain-specific somatostatin receptor rSSTR-4 from a rat genomic library. The deduced amino acid sequence encodes a protein of 384 amino acids and displays structural and sequence homologies with members of the G protein-receptor superfamily. The amino acid sequence of rSSTR-4 is 60% and 48% identical to that of somatostatin receptors SSTR-1 and SSTR-2, respectively, two recently cloned subtypes. Competition curve analysis of the binding properties of the receptor transiently expressed in COS-1 cells revealed a higher apparent affinity for somatostatin 14 than for somatostatin 28. In contrast, the somatostatin analogs SMS 201-995, IM 4-28, and MK-678 failed to displace specific binding in transfected cells. These characteristics resemble the pharmacological binding properties of the previously described brain-specific somatostatin-receptor subtype. Examination of the tissue distribution of mRNA for rSSTR-4 revealed expression limited to various brain regions with highest levels in the cortex and hippocampus. Thus, based on the pharmacology and tissue localization of this receptor, we conclude that rSSTR-4 represents a brain-specific somatostatin receptor.

Amino Acid Sequence↗
PubMed1991

Molecular cloning and sequencing of a cDNA encoding a human alpha 1A adrenergic receptor.

DNA from a rat hippocampus cDNA library and sets of highly degenerate oligonucleotide primers directed toward conserved regions of previously cloned G-protein receptors were used in the polymerase chain reaction to selectively amplify and clone new members of this gene family. A human hippocampus cDNA library was screened with a 610 base pair fragment generated by PCR and a cDNA clone, H318/3, was isolated. The deduced amino acid sequence of this clone encoded a protein of 501 amino acids that showed strong sequence homology to previously cloned G-protein receptors. Nucleotide sequence analysis revealed clone H318/3 was 78% homologous to a rat alpha 1A adrenergic receptor with homology being 95% when comparisons were made in the region that lies between the first to the seventh transmembrane domains. Based on this high degree of sequence homology, we conclude that clone H318/3 represents a cDNA for a human alpha 1A adrenergic receptor.

Amino Acid Sequence↗
PubMed1991

Hormonal regulation of rat hypothalamic neuropeptide mRNAs: effect of hypophysectomy and hormone replacement on growth-hormone-releasing factor, somatostatin and the insulin-like growth factors.

Hormonal feedback regulation of hypothalamic peptides putatively involved in growth hormone (GH) regulation has been studied by measurement of steady-state mRNA levels in male hypophysectomized rats with or without thyroid hormone, corticosterone, testosterone or GH replacement. Hypothalamic GH-releasing factor (GRF) mRNA levels increased progressively following hypophysectomy to 420% of sham levels after 15 days while hypothalamic insulin-like growth factor I (IGF-I) and insulin-like growth factor II (IGF-II) mRNA levels decreased to less than 40% of sham levels. Whole hypothalamic somatostatin mRNA levels were not significantly different from sham. One week of continuous GH infusion restored hypothalamic IGF-I mRNA to levels (95%) indistinguishable from those in sham-operated controls but had no effect on either IGF-II or GRF mRNA. Thyroid hormone, corticosterone and testosterone treatment without GH had no effect on the hypophysectomy-induced reduction of either IGF-I or IGF-II mRNA levels but reversed the elevation of GRF mRNA. We conclude that hypothalamic IGF-I may be involved in GH feedback regulation and thus may function as a hypothalamic modulator of GH. In contrast, IGF-II may be regulated by one of the pituitary trophic hormones but not by GH or the target hormones tested. Finally, hypothalamic GRF mRNA regulation appears to be complex and may include target hormone feedback.

Animals↗
PubMed1991

Pituitary insulin-like growth factor-I content and gene expression in the streptozotocin-diabetic rat: evidence for tissue-specific regulation.

Insulinopenic diabetes mellitus in the rat is associated with reduced circulating levels of insulin-like growth factor-I (IGF-I), resulting primarily from decreased IGF-I synthesis in liver and extrahepatic sites. Plasma GH levels in these animals are also suppressed, with loss of episodic secretion and decreased pituitary synthesis. Intrapituitary IGF-I has been postulated to exert local autocrine/paracrine negative feedback regulation on GH synthesis and secretion. The present studies were designed to examine regulation of pituitary IGF-I peptide content and gene expression in insulinopenic streptozotocin (STZ)-diabetic rats compared to that in liver and testis. Serum IGF-I levels were reduced by 86% in STZ-diabetic rats together with reduction of IGF-I content in liver (53%) and testis (74%; all P less than 0.001 vs. control). Concomitantly, liver and testicular IGF-I mRNA levels were reduced by 90% (P less than 0.001 vs. control). Insulin treatment restored IGF-I peptide levels in serum, liver, and testis toward normal, with a partial but significant increase in liver IGF-I mRNA. In contrast, pituitary IFG-I peptide content increased by 69% in STZ-diabetic rats (P less than 0.001 vs. control), with no change in IGF-I gene expression. Insulin treatment completely reversed the rise of pituitary IGF-I peptide content. These results demonstrate a novel discordance in the regulation of IGF-I gene expression and peptide content between pituitary and other tissues in STZ-induced diabetic rats. Elevated IGF-I levels in the pituitaries of these animals may partly explain the suppressed GH synthesis and secretion seen in STZ-diabetic rats and provide further evidence for a potential autocrine or paracrine role of pituitary IGF-I in GH regulation.

Animals↗
PubMed1991

Regulation of rat hypothalamic preprogrowth hormone-releasing factor messenger ribonucleic acid by dietary protein.

To further evaluate nutrient regulation of GRF synthesis, we measured hypothalamic preproGRF messenger (m) RNA in food-deprived rats refed diets varying in nutrient composition by nuclease protection analysis. Adult male Sprague-Dawley rats were allowed free access to food (Fed), food deprived for 72 h (72-h FD), or 72 h FD then refed for 72 h with either a normal (NF) diet or isocaloric diets containing no protein (PF), carbohydrate (CF), or fat (FF). Seventy-two-hour FD rats displayed the expected 80% reduction in hypothalamic preproGRF mRNA. Upon refeeding, levels were normalized in rats refed NF, CF, or FF diets. In contrast, preproGRF mRNA in rats refed a PF diet was similar to that in 72-h FD rats. Rats refed a PF diet failed to gain weight and consumed less food than animals refed NF, CF, or FF diets. However, the lack of the GRF response to the PF diet was due to protein deprivation rather than caloric restriction, since hypothalamic preproGRF mRNA returned to 66% of Fed values in rats refed an equivalent amount (grams per day) of a NF diet. In 72-h FD rats refed isocaloric diets containing 4%, 8%, or 12% protein, preproGRF mRNA was restored to Fed values in a protein concentration-dependent manner being completely restored by the 12% diet. A lack of dietary protein was sufficient to regulate hypothalamic preproGRF mRNA since feeding rats a PF diet without prior food deprivation resulted in 70% reduction in preproGRF mRNA, whereas CF and FF diets were without effect. These data indicate that decreased hypothalamic preproGRF mRNA expression in 72-h FD rats occurs as a result of dietary protein deprivation.

Animals↗
PubMed1990

Altered pituitary growth hormone (GH) regulation in streptozotocin-diabetic rats: a combined defect of hypothalamic somatostatin and GH-releasing factor.

Diabetes mellitus in the rat is associated with loss of pulsatile GH secretion. An interplay between hypothalamic GH-releasing factor (GRF) and inhibitory factor [somatostatin (SRIF)] secretion is thought to account for episodic pituitary GH release. An increase in SRIF tone/action or a decrease in GRF release/response in diabetic rats could account for the suppressed GH levels. Pituitaries from streptozotocin-diabetic rats contained less GH than controls (15.9 +/- 2.5 vs. 29.5 +/- 4.6 micrograms/mg; P less than 0.05) despite normal somatotrope representation, as demonstrated using immunofluorescence studies. Basal GH secretion from monolayer culture of dispersed anterior pituitary (AP) cells from diabetic rats was proportionately decreased (150 +/- 10 vs. 103 +/- 10 ng/10(5) cells; P less than 0.005). GRF (10(-11)-10(-8) M)-induced release of GH from AP cells was decreased in diabetic rats (maximum response to 10(-8) M GRF, 401 +/- 60 vs. 618 +/- 41 ng/10(5) cells; P less than 0.01); however, sensitivity to GRF was unchanged (EC50, 79 +/- 41 vs. 128 +/- 67 pM). By contrast, SRIF (10(-7)-10(-10)-induced inhibition of GRF (10(-8) M)-mediated GH release was impaired in AP cells of diabetic rats compared to that in controls (IC50, 112 +/- 33 vs. 55 +/- 31 pM; P less than 0.05) associated with a decrease in AP plasma membrane SRIF receptor concentration (63.4 +/- 15.6 vs. 160.3 +/- 13.7 fmol/mg protein; P less than 0.05), with no change in affinity. These findings are consistent with chronic exposure to increased hypothalamic SRIF influence. GH synthesis has been shown to be independent of SRIF regulation; however, insulin-like growth factor-I and GRF inhibit and stimulate GH synthesis, respectively. In diabetic rats insulin-like growth factor-I levels were decreased, appropriate to low GH status, in serum (290 +/- 66 vs. 1662 +/- 92 ng/ml; P less than 0.001) and hypothalamus (6.8 +/- 1.0 vs. 13.0 +/- 0.4 pg/mg wet wt; P less than 0.001) and, thus, did not seem to account for the low AP GH content. Hypothalamic GRF content in diabetic rats (1.11 +/- 0.10 ng/hypothalamus) did not differ from that in controls (1.16 +/- 0.17 ng/hypothalamus). GRF mRNA levels, however, were reduced by 80% in diabetic rats compared to controls. Taken together these data support a combined role for decreased hypothalamic GRF and increased SRIF in mediating alterations of GH synthesis and secretion in streptozotocin-induced diabetes.

Animals↗
PubMed1990

Influence of food deprivation in the rat on hypothalamic expression of growth hormone-releasing factor and somatostatin.

Food deprivation in the rat is associated with a reduction in serum GH levels characterized by suppression of high amplitude GH bursts and a decrease in the duration of secretory episodes. The mechanism(s) mediating this response is unknown. The present studies were designed to evaluate the role of hypothalamic factors potentially responsible for abnormal GH dynamics in food-deprived rats by measuring hypothalamic prepro-GH-releasing factor (GRF) and preprosomatostatin (SRIF) mRNA and peptide levels in adult male Sprague-Dawley rats after 72 h of food deprivation or free access to food. Hypothalamic prepro-GRF mRNA was reduced 80% in food-deprived rats compared to that in fed controls (P less than 0.001), while GRF content was unchanged. Levels of prepro-SRIF mRNA in food-deprived rats were similar to those in controls, as was hypothalamic SRIF content. The time course of hypothalamic prepro-GRF mRNA reduction was determined in groups of rats food-deprived for 24, 48, or 72 h and revealed a significant (30%) reduction of prepro-GRF mRNA (P less than 0.05 vs. fed) by 24 h, with maximal reduction (80%) by 48 h. Refeeding groups of animals for up to 72 h after they had been food-deprived for 72 h resulted in restoration of prepro-GRF mRNA levels to 50% of control levels by 24 h (P less than 0.05 vs. fed) and a return to control values by 48 h. These data suggest that decreased GRF gene expression and possibly GRF release play a major role in the loss of pulsatile GH secretion seen in this model of nutrient deprivation.

Animal Feed↗
PubMed1979

Kinetics of somatostatin inhibition of pentagastrin-stimualted gastric acid secretion.

Dogs with gastric fistulae and denervated gastric pouches received graded doses of pentagastrin with and without a background infusion of somatostatin (1 microgram kg-1 h-1). Similarly, graded doses of somatostatin (0.25, 0.5, 1, 2 and 4 microgram kg-1 h-1) were infused after a steady state gastric secretion had been achieved with pentagastrin (1.5 microgram kg-1 h-1), about twice the dose required to produce half maximal (D50) response. Somatostatin inhibited pentagastrin-stimulated gastric acid secretion with competitive inhibition kinetics, but its precise site of action remains uncertain. The minimum effective dose of somatostatin on a twice D50 dose of pentagastrin was 0.25 microgram kg-1 h-1.

Animals↗
PubMed1979

Growth hormone release inhibitory hormone-like immunoreactivity in pancreas and gut in streptozotocin diabetes in the rat and response to insulin administration.

In streptozotocin diabetes in the rat, growth hormone release-inhibitory hormone-like immunoreactivity (GHRIH-LI) content of pancreas, gastric antrum and colon was increased. Insulin therapy significantly lowered the increased pancreatic GHRIH-LI content but did not affect that of the gastric antrum and colon at the dosage used. The relevance of these findings in relation to pancreatic and gastrointestinal function in diabetes awaits clarification.

Animals↗
PubMed1979

Metabolic clearance and plasma half-disappearance time of exogenous somatostatin in man.

The MCR and half-disappearance time of exogenously administered somatostatin have been measured during and after cessation of a constant infusion. Studies were performed on normal volunteers and patients with chronic liver disease and failure. Immunoreactive somatostatin was measured by a sensitive and specific RIA using an antiserum directed against the core of the molecule. Normal subjects had a mean MCR of 1949 +/- 250 ml/min (28.4 +/- 4.2 ml/min . kg BW) (mean +/- SEM), similar to values found in five patients with chronic liver disease. However, patients with chronic renal failure showed a highly significant (P less than 0.001) lowering of the MCR (501 +/- 32.7 ml/min or 7.8 +/- 0.6 ml/min . kg). The rate of disappearance of somatostatin after infusion was linear for 7-10 min, after which a much slower component was observed. In normal subjects, the t 1/2 of the first component varied from 1.1-3.0 min, in patients with liver disease it varied from 1.2-4.8 min, and in patients with chronic renal failure it varied from 2.6-4.9 min. Exogenously administered somatostatin is rapidly cleared in normal subjects and patients with chronic liver disease, but the MCR in end stage chronic renal failure is markedly lowered. The kidney may have a role in the metabolic clearance of exogenously administered somatostatin, or uremia may impair catabolism nonspecifically.

Adult↗
PubMed1979

Tissue and serum somatostatin-like immunoreactivity in fed, 15-h-fasted, and 72-h-fasted rats.

Somatostatin-like immunoreactivity (SLI) was measured in extracts of gastric antrum, colon, pancreas, and central nervous system, as well as in unextracted portal and inferior vena caval serum from fed, 15-h-fasted, and 72-h-fasted rats. No differences were found in SLI in the central nervous system of the three groups. However, striking variations were found in the gastrointestinal tract and pancreas; the antrum, colon, and pancreas of 15-h-fasted rats contained the least SLI, the content being significantly elevated in these three areas after feeding and after a 72-h fast. Portal serum levels were highest after feeding but lowest in 72-h-fasted rats, in spite of high intestinal and pancreatic SLI content in both. These tissue and serum differences suggest a physiologic role for SLI in nutrient homeostasis not only at tissue level, but also putatively as a hormone in the portal system.

Animals↗
PubMed1978

Circulating antibodies in diabetics treated with conventional and purified insulins.

Conventional insulins contain impurities which are immunogenic; these include pancreatic polypeptide (PP), glucagon and somatostatin and intermediates of insulin synthesis co-extracted during purification. Monocomponent (MC) insulins are free of these contaminants. In 49 insulin-treated diabetic patients, antibodies were found to insulin (94%), pro-insulin (68%) and PP (68%). Antibodies to glucagon and somatostatin were not detected. There was a significantly lower mean maximum binding and titre of insulin and PP antibodies and total circulating insulin (i.e. antibody bound and free) in patients receiving MC insulin. In patients treated with MC insulins for longer than 2 years there was a significant fall in the mean maximum binding of insulin and total serum insulin, but no consistent change in diabetes control and daily insulin dose. It seems that except in the special instances of fat atrophy, insulin allergy and certain cases of insulin resistance, there is no need to resort to MC insulin.

Adolescent↗
PubMed1978

Somatostatin--paracrine and neuromodulator peptide in gut and nervous system.

Somatostatin, a tetradecapeptide widely distributed in nervous tissue and gut, has inhibitory effects on secretion and neuromuscular activity. The actions of this peptide probably embrace three types of transmitter-receptor interaction, namely that of a neurotransmitter in the nervous system, that of a hormone in the hypophyseal portal circulation and that of a local (paracrine) effector in gut and pancreas.

Animals↗