Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Serum-free media containing 10-50 ng insulin, glucagon and epidermal growth factor (EGF) ml-1 stimulate adult rat hepatocyte proliferation in 10-15 day old primary liver cell cultures. The kinetics of this response simulate hepatocellular transitions that accompnay liver regeneration after 67% hepatectomy. Amiloride, a Na+ influx inhibitor, reversibly blocks these transitions in vitro (ID50 approximately 0.02 mM) and in vivo (ID50 approximately 25 mg kg-1). Inhibition is observed with other cation flux modulators, including ouabain (ID50 approximately 0.2 mM), 0.2 microM monensin and 0.2 microM nigericin, but not with 0.3 mM furosemide or tetrodotoxin. The prereplicative interval in culture (0-12 hr) is characterized by preferential cellular responsiveness to EGF (0-3 hr) followed by insulin plus glucagon (3-12 hr). Parallel culture and animal studies show that the amiloride-sensitive and prereplicative intervals coincide. In culture, a "burst" of 22Na+ influx, stimulated by peptide-supplemented media within 1 min but decreased later at 12 hr, is retarded by amiloride. This drug also blocks delayed prereplicative events involving increased amino acid "A" transport system function at 4-8 hr, and 3H-uridine and 3H-leucine incorporation into RNA and protein, respectively, at 8-12 hr. These findings suggest that at least two time-ordered processes are necessary to initiate hepatic growth fully: first, activation of Na+ flux systems by peptides similar or identical to EGF; and second, potentiation of these and subsequent cellular events by the combined action of insulin plus glucagon. [Amiloride: N-amidino-3,5-diamino-6-chloropyrazinecarboxamide; furosemide: 4-chloro-N-furfuryl-5-sulfamoylanthranilic acid; AIB: alpha-aminoisobutyric acid; ID50: administered dose giving 50% inhibition of a maximal response; dFBS: dialyzed fetal bovine serum; L.I.: 3H-dT nuclear labeling index.]
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PMID:Increased sodium ion influx is necessary to initiate rat hepatocyte proliferation. 50 19

Approximately 85% of the filtered bicarbonate load is reabsorbed in the proximal convoluted tubule. Transport in this segment displays saturation kinetics, and exhibits a higher capacity for reabsorption in the earliest portion. Reclamation of bicarbonate is highly regulated in the proximal tubule: an increase in luminal [HCO3-], flow rate and arterial PCO2 increase, while alkalinization of the peritubular surface inhibits bicarbonate absorption. Angiotensin II also appears to regulate bicarbonate transport, especially in the S1 segment. The majority of the filtered bicarbonate load which escapes reabsorption in the proximal tubule is reabsorbed in the thick ascending limb of Henle's loop. Bicarbonate reclamation in this segment is enhanced by luminal [HCO3-] and furosemide, and by chronic metabolic acidosis and increased dietary sodium intake. Amiloride, AVP and glucagon inhibit absorption in the thick ascending limb.
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PMID:Reclamation of filtered bicarbonate. 217 15

alpha 2-Adrenoceptor agonists inhibit glucose-stimulated insulin release and glucose utilization in pancreatic islets. In isolated pancreatic islets of the rat, the Ca2+ channel agonists CGP-28392 and BAY-K-8644 increased insulin release in the presence of clonidine. Neither CGP-28392 nor BAY-K-8644 antagonized the effect of clonidine on glucose utilization. The Ca2+ ionophore, ionomycin, also did not affect glucose utilization in the presence or absence of clonidine. Glucagon partly reversed the effects of clonidine on insulin release, and it potentiated glucose-stimulated insulin release in the absence of clonidine. Glucagon reversed the effects of clonidine on glucose utilization. Amiloride antagonized the effects of clonidine on insulin secretion but did not enhance markedly glucose utilization in the presence or absence of clonidine. Carbamylcholine and arecoline reversed the effects of clonidine on glucose utilization and partly reversed the effects on insulin release in the absence of extracellular Ca2+. Prostaglandin (PG) E2, but not PGF2 alpha, inhibited glucose utilization in a time- and concentration-dependent manner. PGE2 also inhibited glucose-stimulated insulin release. Pertussis toxin blocked both actions of PGE2. The cyclooxygenase inhibitor indomethacin did not affect insulin release or glucose utilization in the presence of clonidine. Thus, elevated intracellular Ca2+ levels antagonize the effects of clonidine on insulin release, whereas other mediators appear to be required to alter glucose utilization.
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PMID:Calcium mobilization, prostaglandin E2 and alpha 2-adrenoceptor modulation of glucose utilization and insulin secretion in pancreatic islets. 254 83

The effects of amiloride and of natural aliphatic polyamines on basal and hormone-stimulated protein phosphorylations in hepatocytes were studied. Cells isolated from adult rats were incubated in suspension with (32P)-orthophosphate, in the absence or presence of the effectors at varying concentrations and for different times; hepatocytes were then exposed to various hormones for 10 min. Phosphoproteins contained in total cell lysates were analyzed by one- and two-dimensional gel electrophoresis and autoradiography. Amiloride and spermine (the most effective amine) decreased the basal level of phosphorylation of proteins of 46, 34 and 22 kDal, and increased that of 18 kDal and 93 kDal proteins. These effects were maximal with external concentrations of 1 mM and 7.5-10 mM amiloride and spermine, respectively. They were detectable after a lag period of about 10 min and reached a plateau after 45 min. Pretreatment of cells with these effectors almost completely prevented stimulation of the phosphorylation of the 46 and 34 kDal proteins by insulin. In contrast, the effects of vasopressin on the same proteins were only partly inhibited, whereas those of glucagon appeared largely unaffected. The major effect observed in intact cells (i.e., decreased phosphorylation) could be reproduced in a cell-free system where no kinase activity persisted. Amiloride or spermine added directly to cell extracts strongly accelerated the dephosphorylation of 46 kDal protein and also of the 61 kDal protein identified as pyruvate kinase. Furthermore, restoration of the activity of this enzyme occurred concomitantly with dephosphorylation of the 61 kDal protein, an observation supporting the notion that amiloride and spermine could activate a phosphoprotein phosphatase.
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PMID:Insulin regulation of protein phosphorylation in hepatocytes. Studies using two effectors: amiloride and natural aliphatic polyamines. 390 16

Insulin and glucagon stimulate amino acid transport in isolated rat hepatocytes. Amiloride, a specific Na+-influx inhibitor, completely inhibited the hormonal (glucagon or insulin) stimulation of alpha-aminoisobutyric acid influx by preventing the emergence of a high-affinity transport component. The drug also inhibited [14C]valine incorporation into hepatocyte protein. The half-maximal concentration of amiloride for inhibition of protein synthesis was similar to that required for inhibition of hormone-stimulated amino acid transport (approx. 0.1 mM). In primary cultured rat hepatocytes, amiloride markedly depressed the stimulation of alpha-aminoisobutyric acid transport by glucagon, or a mixture of glucagon, insulin and epidermal growth factor. These results suggest that amiloride inhibits the hormonal stimulation of hepatocyte amino acid transport by preventing the synthesis of high-affinity transport proteins. They also suggest that the hormonal stimulation of hepatocyte amino acid transport is dependent, at least partly, on Na+ influx.
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PMID:The effect of amiloride on hormonal regulation of amino acid transport in isolated and cultured adult rat hepatocytes. 626 11

The effects of insulin and glucagon on the (Na+-K+)-ATPase transport activity in freshly isolated rat hepatocytes were investigated by measuring the ouabain-sensitive, active uptake of 86Rb+. The active uptake of 86Rb+ was increased by 18% (p less than 0.05) in the presence of 100 nM insulin, and by 28% (p less than 0.005) in the presence of nM glucagon. These effects were detected as early as 2 min after hepatocyte exposure to either hormone. Half-maximal stimulation was observed with about 0.5 nm insulin and 0.3 nM glucagon. The stimulation of 86Rb+ uptake by insulin occurred in direct proportion to the steady state occupancy of a high affinity receptor by the hormone (the predominant insulin-binding species in hepatocytes at 37 degrees C. For glucagon, half-maximal response was obtained with about 5% of the total receptors occupied by the hormone. Amiloride (a specific inhibitor of Na+ influx) abolished the insulin stimulation of 86Rb+ uptake while inhibiting that of glucagon only partially. Accordingly, insulin was found to rapidly enhance the initial rate of 22Na+ uptake, whereas glucagon had no detectable effect on 22Na+ influx. These results indicate that monovalent cation transport is influenced by insulin and glucagon in isolated rat hepatocytes. In contrast to glucagon, which appears to enhance 86Rb+ influx through the (Na+-K+)-ATPase without affecting Na+ influx, insulin stimulates Na+ entry which in turn may increase the pump activity by increasing the availability of Na+ ions to internal Na+ transport sites of the (Na+-K+)-ATPase.
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PMID:Insulin and glucagon stimulation of (Na+-K+)-ATPase transport activity in isolated rat hepatocytes. 626 50

Recent research has provided new concepts in our understanding of renal magnesium handling. Although the majority of the filtered magnesium is reabsorbed within the loop of Henle, it is now recognized that the distal tubule also plays an important role in magnesium conservation. Magnesium absorption within the cTAL segment of the loop is passive and dependent on the transepithelial voltage. Magnesium transport in the DCT is active and transcellular in nature. Many of the hormonal (PTH, calcitonin, glucagon, AVP) and nonhormonal (magnesium-restriction, acid-base changes, potassium-depletion) influences that affect magnesium transport within the cTAL similarly alter magnesium absorption within the DCT. However, the cellular mechanisms are different. Actions within the loop affect either the transepithelial voltage or the paracellular permeability. Influences acting in the DCT involve changes in active transcellular transport either Mg2+ entry across the apical membrane or Mg2+ exit from the basolateral side. These transport processes are fruitful areas for future research. An additional regulatory control has recently been recognized that involves an extracellular Ca2+/Mg(2+)-sensing receptor. This receptor is present in the basolateral membrane of the TAL and DCT and modulates magnesium and calcium conservation with elevation in plasma divalent cation concentration. Further studies are warranted to determine the physiological role of the Ca2+/Mg(2+)-sensing receptor, but activating and inactivating mutations have been described that result in renal magnesium-wasting and hypermagnesemia, respectively. All of these receptor-mediated controls change calcium absorption in addition to magnesium transport. Selective magnesium control is through intrinsic control of Mg2+ entry into distal tubule cells. The cellular mechanisms that intrinsically regulate magnesium transport have yet to be described. Familial diseases associated with renal magnesium-wasting provide a unique opportunity to study these intrinsic controls. Loop diuretics such as furosemide increase magnesium excretion by virtue of its effects on the transepithelial voltage thereby inhibiting passive magnesium absorption. Distally acting diuretics, like amiloride and chlorothiazide, enhance Mg2+ entry into DCT cells. Amiloride may be used as a magnesium-conserving diuretic whereas chlorothiazide may lead to potassium-depletion that compromises renal magnesium absorption. Patients with Bartter's and Gitelman's syndromes, diseases of salt transport in the loop and distal tubule, respectively, are associated with disturbances in renal magnesium handling. These may provide useful lessons in understanding segmental control of magnesium reabsorption. Metabolic acidosis diminishes magnesium absorption in MDCT cells by protonation of the Mg2+ entry pathway. Metabolic alkalosis increases magnesium permeability across the cTAL paracellular pathway and stimulates Mg2+ entry into DCT cells. Again, these changes are likely due to protonation of charges along the paracellular pathway of the cTAL and the putative Mg2+ channel of the DCT. Cellular potassium-depletion diminishes the voltage-dependent magnesium absorption in the TAL and Mg2+ entry into MDCT cells. However, the relationship between potassium and magnesium balance is far from clear. For instance, magnesium-wasting is more commonly found in patients with Gitelman's disease than Bartter's but both have hypokalemia. Further studies are needed to sort out these discrepancies. Phosphate deficiency also decreases Mg2+ uptake in distal cells but it apparently does so by mechanisms other than those observed in potassium depletion. Accordingly, potassium depletion, phosphate deficiency, and metabolic acidosis may be additive. The means by which cellular potassium and phosphate alter magnesium handling are unclear. Research in the nineties has increased our understanding of renal magnesium transport and regulation, but there are many in
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PMID:Renal magnesium handling: new insights in understanding old problems. 935 Jun 41