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)

In this study a synthetic analog of the calmodulin-binding domain of myosin light chain kinase, a 17-amino-acid peptide (M5) was used to examine the possible role of calmodulin in melanotropin receptor function. Binding of beta-melanocyte-stimulating hormone to its membrane receptor and subsequent stimulation of adenylate cyclase (AC) were found to be specifically inhibited by M5 in a dose-dependent and noncompetitive manner, both in intact M2R melanoma cells and in a plasma membrane preparation derived thereof. Half-maximal inhibition of both hormone binding and melanotropin-sensitive AC activity was shown to occur at approximately 1 microM M5. In contrast, stimulation of AC by prostaglandin E1, guanosine 5'-O-(3-thio)triphosphate, forskolin, and unstimulated enzyme activity were unaffected by the presence of M5, under the same assay conditions. Furthermore, addition of a molar excess of calmodulin to the AC assay completely abolished the inhibitory effects of the peptide on melanotropin-stimulated AC activity. Other peptides of similar size, which bind to calmodulin with low affinity (e.g. glucagon, somatostatin, and vasoactive intestinal peptide), were shown to be totally ineffective in inhibiting melanotropin-sensitive AC. These findings, along with those shown previously for other antagonists of calmodulin, suggest a role for an M5-binding protein, as of yet unidentified, involved in the regulation of the melanotropin receptor function.
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PMID:A synthetic analog of the calmodulin-binding domain of myosin light chain kinase inhibits melanotropin receptor function and activation of adenylate cyclase. 336 68

Glucagon is a vasodilator substance that reduces blood pressure via a decreased vascular resistance in the splanchnic and hepatic vasculature. Species differences in the response of various vascular beds to glucagon have been documented. In the kidney, glucagon in relatively large doses increased renal plasma flow, glomerular filtration, and electrolyte excretion. It has been shown that intraarterial injection of glucagon into the renal artery can produce an increase in electrolyte excretion on the side that received an injection with minimal or no changes in glomerular filtration. This indicated a direct tubular effect of this polypeptide. This effect may be related to the increased glomerular filtration observed in poorly controlled diabetics where insulin concentrations are low and glucagon concentrations are high. The tubular effects of glucagon are probably mediated via cAMP and prostaglandin formation in renal tubular cells, especially the ascending limbs of Henle and collecting ducts. Glucagon increases the RNA concentration in glomerular tissue, and this effect is probably independent of cAMP. The latter effect of glucagon has been related to the glomerular enlargement and membrane thickening observed in poorly controlled insulin-dependent diabetics. Starvation natriuresis has been related to increased concentrations of glucagon in blood. The likely mechanism is that glucagon increased the renal excretion of organic acids, possibly by inhibiting the renal tubular reabsorption of these acids. Little is known concerning the effects of glucagon on the cAMP content of vascular smooth muscle. Indirect evidence suggests that such effects may be mediated via the production of cAMP. If this can be established, it would be likely that the glucagon-induced vasodilation is due to a cAMP-dependent phosphorylation of the myosin light chain kinase. This kinase shows reduced sensitivity to the Ca++ calmodulin complex when it is phosphorylated by the cAMP-dependent kinase and thus may produce relaxation of smooth muscle. In cardiac muscle, glucagon produced positive inotropic and chronotropic effects. These effects show species differences and in some species activate only the auricle with minimal effects of ventricular muscle. The effects of glucagon in general resemble those of a beta-adrenergic agent; however, glucagon seems to be nonarrhythmogenic in a variety of cardiac preparations and its effects are not blocked by propranolol. In some of these experimental conditions the chronotropic effects of glucagon play an important role in the antiarrhythmogenic effects, although direct cardiac membrane effects have been postulated. Several factors can modify the
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PMID:Glucagon and the circulation. 631 31

Calmodulin (CaM) binding by turkey gizzard myosin light chain kinase (MLCK) causes subtle changes in the fluorescence emission and polarization excitation spectra of the enzyme. Fluorescence experiments using 9-anthroyl-choline (9AC), which competes with ATP in binding, demonstrate mutually stabilizing interactions between the CaM and ATP binding sites corresponding to delta G = -0.6 to -0.7 kcal/mol. Fluorescence titrations in the presence of 9AC or 5,5'-bis[8-(phenylamino)-1-naphthalenesulfonate] confirm the stoichiometry of 1 mol of CaM/MLCK. Phosphorylation of MLCK has no effect on either the protein fluorescence or the binding of ATP and 9AC. The dissociation constant for the MLCL-CaM complex is increased approximately 500-fold on phosphorylation. Values of Kd for the phosphorylated enzyme range from 0.5 to 1.1 microM in 0.2 N KCl, pH 7.3, 25 degrees C. We showed competition between MLCK and other CaM binding proteins and peptides by using both fluorescence and catalytic activity measurements. Competition for CaM occurs with ACTH, beta-endorphin, substance P, glucagon, poly(L-arginine), myelin basic protein, troponin I, and histone H2A. Phosphorylation of the last three proteins by the adenosine cyclic 3',5'-phosphate dependent protein kinase diminishes their ability to compete. Phosphorylation of MLCK by the protein kinase gives 0.95 +/- 0.04 and 2.2 +/- 0.4 mol of incorporated 32P in the presence and absence of CaM, respectively. These stoichiometries agree with those recently reported [Conti, M. A. & Adelstein, R. S. (1981) J. Biol. Chem. 256, 3178].
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PMID:Functional interactions between smooth muscle myosin light chain kinase and calmodulin. 689 95

To assess the role of cAMP in the regulation of autophagy, we examined the effects of cAMP analogues and cAMP-elevating agents on freshly isolated rat hepatocytes, using electroinjected [3H]raffinose as an autophagy probe. Glucagon was found to stimulate, inhibit or have no effect on autophagy, depending on the inclusion of metabolites like pyruvate (which caused ATP depletion and autophagy suppression) and amino acids (a complete mixture that antagonized pyruvate) in the incubation medium. Inhibition was also observed with theophylline, a cAMP-elevating inhibitor of cyclic nucleotide phosphodiesterases, and with the adenylyl cyclase activator deacetylforskolin. At low concentrations of deacetylforskolin, the inhibition could be abolished by amino acids. N6,2'-O-Dibutyryladenosine 3',5'-monophosphate (Bt2-cAMP) strongly inhibited both autophagic sequestration of [3H]raffinose and overall autophagic protein degradation; again, amino acids abolished the autophagy-inhibitory effect of low Bt2-cAMP concentrations. Several other cAMP analogues (8-thiomethyl-cAMP, N6-benzoyl-cAMP, (S)-5,6-dichloro-1-D-ribofuranosylbenzimidazole 3',5'-[thio]monophosphate, (S)-8-bromoadenosine 3',5'-[thio]monophosphate) inhibited autophagy as well. The effect of Bt2-cAMP was rapid, dose-dependent, reversible and did not require concomitant protein synthesis. Neither Bt2-cAMP nor deacetylforskolin reduced intracellular ATP levels or cell viability, ruling out inhibition of autophagy by non-specific cytotoxicity. The autophagy-inhibitory effect of Bt2-cAMP could be substantially antagonized (40-50%) by KT-5720, a specific inhibitor of the cAMP-dependent protein kinase A, and by the nonspecific protein kinase inhibitor K-252a. Somewhat surprisingly, KN-62 and KT-5926, allegedly specific inhibitors of Ca2+/calmodulin-dependent protein kinase II and myosin light chain kinase, respectively, were also Bt2-cAMP-antagonistic. These results suggest that cAMP regulates the early, sequestrational step of hepatocytic autophagy by a highly conditional, dual mechanism, inhibition being predominant under most conditions in freshly isolated hepatocytes, whereas stimulation reportedly predominates in vivo. The effect of cAMP is probably mediated by protein kinase A, but other protein kinases would appear to participate in the regulation of autophagic sequestration as well.
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PMID:Role of cAMP in the regulation of hepatocytic autophagy. 861 61

The gut is a complex organ that has played an important role in digestion, absorption, endocrine functions, and immunity. The gut mucosal barriers consist of the immunologic barrier and nonimmunologic barrier. During critical illnesses, the gut is susceptible to injury due to the induction of intestinal hyperpermeability. Gut hyperpermeability and barrier dysfunction may lead to systemic inflammatory response syndrome. Additionally, gut microbiota are altered during critical illnesses. The etiology of such microbiome alterations in critical illnesses is multifactorial. The interaction or systemic host defense modulation between distant organs and the gut microbiome is increasingly studied in disease research. No treatment modality exists to significantly enhance the gut epithelial integrity, permeability, or mucus layer in critically ill patients. However, multiple helpful approaches including clinical and preclinical strategies exist. Enteral nutrition is associated with an increased mucosal barrier in animal and human studies. The trophic effects of enteral nutrition might help to maintain the intestinal physiology, prevent atrophy of gut villi, reduce intestinal permeability, and protect against ischemia-reperfusion injury. The microbiome approach such as the use of probiotics, fecal microbial transplantation, and selective decontamination of the digestive tract has been suggested. However, its evidence does not have a high quality. To promote rapid hypertrophy of the small bowel, various factors have been reported, including the epidermal growth factor, membrane permeant inhibitor of myosin light chain kinase, mucus surrogate, pharmacologic vagus nerve agonist, immune-enhancing diet, and glucagon-like peptide-2 as preclinical strategies. However, the evidence remains unclear.
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PMID:Pathophysiology and protective approaches of gut injury in critical illness. 3302 4