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Biomedical subjects

M J Lewin

Publications and source records attributed to M J Lewin.

At least 109 records · Page 6Linked to original sources
PubMed1982

Intracellular receptor for somatostatin in gastric mucosal cells: decomposition and reconstitution of somatostatin-stimulated phosphoprotein phosphatases.

Using 32P-labeled histone as exogenous substrate, we showed a potent stimulatory effect of somatostatin on cytosolic phosphoprotein phosphatases (PPPases; phosphoprotein phosphohydrolase, EC 3.1.3.16) in rat gastric mucosal cells. Partial purification of cytosolic fraction in DEAE-Sephadex ion-exchange chromatography and further gel filtration on Sephadex C-75 and Sephadex G-100 separated somatostatin-dependent PPPases into three distinct molecular species. One corresponding to Mr 130,000 was devoid of any PPPase activity but specifically bound [Tyr1]somatostatin 125I-labeled on the Tyr ([125I-Tyr1]somatostatin) with an apparent equilibrium dissociation constant of 3 x 10(-10) M. The two other molecular species corresponded to Mrs 64,000 and 13,000. They produced catalytic dephosphorylation of 32P-labeled histone, but they were not sensitive to somatostatin and did not show any specific binding to radiolabeled hormone. Mixing of the larger with either of the two smaller molecular species resulted in concentration -dependent inhibition of PPPase activity. However this inhibition was reversed by increased concentrations of somatostatin, with the concentration for half-maximal reactivation on being close to 0.1 nM. Furthermore somatostatin stimulation in reconstituted materials developed according to a rapid time course (t1/2, less than 5 sec), consistent with that observed for binding of [125I-Tyr1]somatostatin. These results strongly argue for the presence of an intracellular somatostatin receptor in gastric mucosal cells and characterize this receptor as a PPPase regulatory subunit. Thus, substrate dephosphorylation could be the primary event triggering physiological effects of somatostatin in stomach and perhaps other organs of the digestive tract [Reyl, F. & Lewin, M. J.l M. (1981) Biochim. Biophys. Acta 675, 297-300].

Animals↗
PubMed1980

C1-transport in gastric micorsomes. An ATP-dependent influx sensitive to membrane potential and to protein kinase inhibitor.

Uptakes of radioactive C1- or 1- by gastric microsomal vesicles were stimulated 2- to 8-fold by AtP. The sensitivity of those uptakes to a C1- in equilibrium OH- ionophore and to osmotic swelling suggested they were due to transport rather than to binding. The ATP effect was labile, but dithiothreitol and methanol improved its stability. The stimulation of anion transport required magnesium; GTP and UTP were less potent than ATP whereas ADP and AMP had no effect. The apparent Km for ATP was estimated to be 2 X 10(-4) M at 22 degrees C. The rate of the ATP-dependent transport showed saturation-type kinetics, with half-maximal uptake at 10 mM for I- and 15 mM for C1-. Nonradioactive C1-, I-, and SCN- competed with 125I- uptake while SO42- did not. K+ valinomycin increased the ATP-dependent C1- uptake. The thermostable inhibitor of cAMP-dependent protein kinases inhibited the effect of ATP. These results suggest the existence of an anion conductance, permeant to C1-, I-, and SCN- and nonpermeant to SO42-, which could be linked to a cAMP-dependent protein kinase.

Adenosine Triphosphate↗
PubMed1980

Specific activation of cyclic AMP-dependent protein kinase(s) by H2-histamine agonists in isolated gastric mucosal cells from guinea-pig.

Histamine stimulated cyclic AMP-dependent protein kinase activity in dispersed mucosal cells from guinea-pig gastric fundus (Ka = 5 microM). The H2-agonists dimaprit and impromidine produced similar effects, while the H1-agonist 2-(2-pyridyl) ethylamine had only a weak one. The H2-antagonist cimetidine competitively inhibited 0.1 mM histamine stimulation (Ki = 2 microM). In contrast, the H1-antagonist diphenhydramine had no effect up to 1 mM.

Animals↗
PubMed1978

Gastrin cell distribution in normal human stomachs and in patients with Zollinger-Ellison syndrome.

Quantitative distribution of gastrin cells was evaluated in three normal human stomachs and in four stomachs from patients with Zollinger-Ellison syndrome. Cells identified by the immunoperoxidase method were counted along the entire length of five mucosal strips parallel to the axis of the lesser curvature and sampled from the posterior to the anterior walls. The number of cells per unit area (2300 microns2) decreased from the pylorus to the borderline of the gastric body from (mean +/- SEM) 50.9 +/- 12.0 to 24.2 +/- 13.0 and from 29.6 +/- 5.6 to 10.4 +/- 2.6 for control and Zollinger-Ellison syndrome, respectively, with large interindividual variations. From factorial analysis no statistical difference was found between the two groups. It is therefore suggested that the number of gastrin cell in antral mucosa may not be a significant criteria in the diagnosis of Zollinger-Ellison syndrome.

Aged↗
PubMedDate not supplied

Endogenous opioid peptides in the control of food intake in cats.

In this report, we investigated the role of exogenous and endogenous enkephalins on food intake in the cat, using, respectively, exogenous [D-Ala2-Met5]-enkephalin (DAME) and acetorphan (Ac) in order to inhibit the degradation of endogenous enkephalins. In addition, the selective peripheral antagonist naltrexone methylbromide (NTxMB) and the nonselective antagonist naloxone (Nx) were used in an attempt to discriminate central and peripheral opioid receptors. In 18-hours food-deprived animals, Ac (5 mg/kg IV) increased milk intake during sham feeding (+18%, p less than 0.05), but did not modify it in feeding conditions. Nx (1 mg/kg SC) reduced milk intake in sham-feeding experiments (-67%, p less than 0.01) more than in milk-feeding conditions (-30%, p less than 0.01). NTxMB (1 mg/kg SC) did not modify milk intake in sham-feeding but decreased it in feeding experiments. In nonfasted animals, Ac did not modify food intake. IV infusion of DAME (50 micrograms/kg) resulted in a reduction of daily food intake (-32%, p less than 0.01). Nx (1 mg/kg SC) decreased the earlier 30 min intake followed by reduction of daily intake (-30%, p less than 0.01). NTxMB (1 and 4 mg/kg SC) increased the 30-min intake dose dependently, without significant change in daily intake. In conclusion, Ac increases food intake in sham-feeding conditions, suggesting that endogenous enkephalins are likely to be involved in the stimulation of food intake. The effects of Nx and NTxMB furthermore suggest both a central activation, and a peripheral inhibition of food intake by opiates when food is allowed to proceed normally through the digestive tract.

Animals↗
PubMedDate not supplied

The gastric H3 receptor: a review.

Previous in vivo and in vitro studies from our laboratory have revealed a line of pharmacological evidence supporting histamine H3 receptor(s) involvement in the control of gastric acid secretion. We have recently extended our studies to the human gastric tumoral cell HGT-1. This cell was found to contain an H3 receptor inhibiting basal and carbachol-stimulated inositol phosphate formation. Furthermore, we were able to solubilize and affinity-purify this receptor in the form of a single 70 kDa protein. These findings are the first biochemical description of the H3 receptor subtype and the first direct demonstration that this subtype can occur on a non-neural cell. Furthermore, they provide a molecular basis to explain its suggested inhibitory role in gastric physiology.

Animals↗
PubMedDate not supplied

Cell physiology and pharmacology of gastric acid secretion.

Our stomach produces daily a large amount of hydrochloric acid at a pH close to 1. This secretion represents a more than one million-fold in H+ ion concentration as compared to blood and intracellular medium of a pH of 7.4. It is due to a specialized cell, the parietal cell, which contains a unique transport enzyme, the (H+, K+)-ATPase. The parietal cell is itself under the control of several endocrine and paracrine stimuli operating through appropriate receptors. The recent progresses achieved in the knowledge of these key elements of the acid secretion mechanism had led to the development of specific and potent inhibitors of crucial interest in the treatment of ulcer disease and reflux oesophagitis such as histamine H2 and (H+, K+)-ATPase antagonists.

Gastric Acid↗
PubMedDate not supplied

H3-receptor regulation of vascular gastrin and somatostatin releases by the isolated rat stomach.

We have studied the effects of the H3-receptor agonist (R) alpha-methylhistamine [(R) alpha-MeHA] and the H3-receptor antagonist thioperamide (Thiop) on basal- and carbachol-stimulated vascular gastrin release (GR) and somatostatin release (SR) by the isolated rat stomach. Carbachol dose-dependently stimulated and inhibited GR and SR, respectively. Maximal stimulation of GR (500 +/- 112 percent of basal; p < .01), and maximal inhibition of SR (-62 +/- 9 percent under basal; p < .01) were obtained with 1 micron carbachol. Neither (R)alpha-MeHA nor Thiop, up to 10 microns, affected GR. However, SR was dose-dependently enhanced by Thiop (25 +/- 8 percent for 10 microns). Carbachol stimulation of GR was strongly inhibited by Thiop (30 +/- 7 percent for 100 nM and 73 +/- 14 percent for 1 microgram), whereas it was potentiated by (R)alpha-MeHA. Carbachol inhibition of SR was reversed by Thiop and (R)alpha-MeHA. However, the reversal effect of (R)alpha-MeHA was prevented by the CCKB/gastrin receptor antagonist PD134308. These results support H3-receptor regulation of basal and cholinergically-stimulated GR and SR.

Animals↗
PubMedDate not supplied

[Stimulation of adenylate cyclase by the isoforms of human and rat beta-3 adrenergic receptor expressed in the CHO cells].

OBJECTIVES AND METHOD: The beta 3 adrenergic receptor stimulates lipolysis and colonic relaxation in the rat, and, suggestively, in man. Several human forms generated by different mRNA splicings can occur: the A form of 396 amino acids and the B and C forms extended by 12 and 6 amino acids respectively, in the C-terminus region. In order to characterize these different forms as expressed in CHO cells, we studied adenylyl cyclase stimulation by the beta 3 agonists, SR58611A and BRL37344 and its inhibition by the beta 3 antagonist SR59230. RESULTS: This antagonist totally inhibited SR58611-adenylyl cyclase stimulation with the following hierarchy of potency: C form >> B > A. In rat, a unique form is expressed which is close to the human B form. This form was the less sensitive to beta 1 and beta 2 antagonists. CONCLUSION: These findings constitute a molecular pharmacological basis for the design of beta 3 agonists of therapeutic value.

Adenylyl Cyclases↗
PubMedDate not supplied

Is gastrinoma a medical disease?

Zollinger-Ellison syndrome (ZES) is a rare disease. Its management concerns symptoms related to the gastric acid overproduction that characterizes the syndrome and to the gastrin-producing tumor(s) usually located in the duodenal wall and/or the endocrine pancreas. Acid hypersecretion is now controlled by the use of powerful antisecretory agents. Management of the malignant process(es) has become the primary goal of modern strategy: it aims first at curing the disease and second at prolonging patient survival by prevention of hepatic metastasis. In patients with the sporadic form of the disease and without liver metastases, it is currently possible to localize and to surgically remove the endocrine tumor(s). This progress has been made feasible by refinements in modern medical imaging. At present, however, disease cure, even in the most favorable conditions, is not be greater than 30 to 50 percent at five years. In patients with ZES integrated in the context of multiple endocrine neoplasia type I, disease cure rate is extremely low, although occasional patient survival can be as good or even better than in the sporadic group. Disseminated malignancy (liver and/or extra-abdominal lymph nodes or bone localization) remains the principal determinant of early death. Surgical treatment is usually precluded in such cases. Liver transplantation has not been successful in these patients.

Endoscopy↗