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)

Controversy exists concerning the localization of the enzyme Na+,K(+)-ATPase to canalicular membranes in hepatocytes. Most studies find enzyme activity only at the basolateral plasma membrane domain of the hepatocyte. However, Na+,K(+)-ATPase activity has been detected recently in a canalicular membrane fraction prepared by Mg++ precipitation, suggesting that differences in membrane domain fluidity account for these discrepancies. To reinvestigate this question, we used free-flow electrophoresis to further purify canalicular liver plasma membranes originally separated by sucrose density centrifugation. With this technique, canalicular membranes devoid of Na+,K(+)-ATPase activity by routine assay were separated into six subfractions. More than 80% of the activities of canalicular marker enzymes was recovered in two subfractions closest to the anode, which were totally devoid of Na+,K(+)-ATPase activity. However, Na+,K(+)-ATPase activity could now be detected in the four other fractions that contained only small amounts of canalicular marker enzymes. The basolateral marker enzyme, glucagon-stimulated adenyl cyclase, comigrated with this cryptic Na+,K(+)-ATPase activity. Furthermore, addition of 6 mumol/L [12-(2-methoxyethoxy)-ethyl-8-(cis-2-n-octylcyclopropyl)-octanoate ], a membrane-fluidizing agent, to the original canalicular membrane preparation and to all subfractions did not stimulate or unmask latent Na+,K(+)-ATPase activity. Finally, when canalicular membranes isolated by Mg++ precipitation were subjected to free-flow electrophoresis, they could not be separated from the more positively charged Na+,K(+)-ATPase-containing fractions, probably because of alterations in surface charge. Together these findings suggest that Na+,K(+)-ATPase is a basolateral enzyme, that represents a small contaminant when present in canalicular liver plasma membranes and that methodological differences may account for previous discrepancies.
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PMID:Cryptic Na+,K(+)-ATPase activity in rat liver canalicular plasma membranes: evidence for its basolateral origin. 215 68

In this immunocytochemical study, we have analyzed the developmental profile and phenotypic expression of the endocrine cell antigens chromogranin, 5-hydroxytryptamine, gastrin/cholecystokinin, cholecystokinin (9-20), somatostatin, somatostatin 28 (1-14), somatostatin cryptic peptide, glucagon, glucagonlike peptides 1 and 2, glicentin, peptide YY, glucose-dependent insulinotropic peptide, secretin, neurotensin, and substance P in human fetal stomach and intestine. All currently identifiable endocrine cell types were detected by 10 wk of gestation. Immunostaining for the endocrine cell marker chromogranin revealed abundant endocrine cells in the earliest specimens (8 wk of gestation) with a relatively higher frequency in both proximal duodenum and distal colon/rectum compared with other areas. Quantification of endocrine cells showed an increase with age that was roughly parallel to the growth of the gut as a whole. These studies show that the diversity of the endocrine component of the gut appears to be established by 10 wk of gestation and that gut activity is preceded by the development of a fully differentiated endocrine component, which may subserve or even initiate the onset of functional maturity.
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PMID:Developmental profile of chromogranin, hormonal peptides, and 5-hydroxytryptamine in gastrointestinal endocrine cells. 272 79

Membrane proteins of transporting epithelia are often distributed between apical and basolateral surfaces to produce a functionally polarized cell. The distribution of Na+,K+-ATPase [ATP phosphohydrolase (Na+/K+-transporting), EC 3.6.1.37] between apical and basolateral membranes of hepatocytes has been controversial. Because Na+,K+-ATPase activity is fluidity dependent and the physiochemical properties of the apical membrane reduces its fluidity, we investigated whether altering membrane fluidity might uncover cryptic Na+,K+-ATPase in bile canalicular (apical) surface fractions free of detectable Na+,K+-ATPase and glucagon-stimulated adenylate cyclase activities. Apical fractions exhibited higher diphenylhexatriene-fluorescence polarization values when compared with sinusoidal (basolateral) membrane fractions. When 2-(2-methoxyethoxy)ethyl 8-(cis-2-n-octylcyclopropyl)octanoate (A2C) was added to each fraction, Na+,K+-ATPase, but not glucagon-stimulated adenylate cyclase activity, was activated in the apical fraction. In contrast, further activation of both enzymes was not seen in sinusoidal fractions. The A2C-induced increase in apical Na+,K+-ATPase approached 75% of the sinusoidal level. Parallel increases in apical Na+,K+-ATPase were produced by benzyl alcohol and Triton WR-1339. All three fluidizing agents decreased the order component of membrane fluidity. Na+,K+-ATPase activity in each subfraction was identically inhibited by the monoclonal antibody 9-A5, a specific inhibitor of this enzyme. These findings suggest that hepatic Na+,K+-ATPase is distributed in both surface membranes but functions more efficiently and, perhaps, specifically in the sinusoidal membranes because of their higher bulk lipid fluidity.
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PMID:Biochemical localization of hepatic surface-membrane Na+,K+-ATPase activity depends on membrane lipid fluidity. 284 69

Although gastric inhibitory peptide (GIP) has never been detected outside the upper small intestine by immunochemical methods, GIP-like immunoreactivity has been demonstrated by immunocytochemistry in the glucagon/glicentin cells of pancreas, and gut. In the present study several GIP antisera (five polyclonal and one monoclonal) were tested on specimens from pancreas and intestines of several mammalian species, including man. Two of the polyclonal antisera and the monoclonal one stained cells in the upper small intestine only, while the other three also stained cells in the pancreas, ileum, and colon. Monoclonal anti-GIP did not stain GIP cells in man. The immunostaining produced could not be abolished by pretreatment of the antisera with glucagon or glicentin in excess, whereas small amounts of synthetic or natural porcine GIP prevented the immunostaining. Thus, three of the antisera are specific for GIP, while the other three recognize not only GIP but also GIP-like peptides. The results suggest that the glucagon/glicentin cells contain peptides distinct from GIP but sharing an immunodeterminant with GIP. The GIP-like immunoreactivity in the glucagon cells of the rat pancreas was not altered by infusion of GIP or by elimination of the bulk of endogenous GIP by resection of the upper small intestine, indicating that the GIP-like peptide is produced in the glucagon cells rather than accumulated from the circulation. The nature of this GIP-like peptide is unknown. Conceivably, it represents the cryptic portion of the glucagon precursor molecule. In some species a proportion of the GIP cells in the proximal small intestine displayed glicentin-like immunoreactivity as well, emphasizing the relationship between GIP cells on the one hand and glucagon/glicentin cells on the other.
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PMID:Gastric inhibitory peptide-like immunoreactivity in glucagon and glicentin cells: properties and origin. An immunocytochemical study using several antisera. 618 83

To address the origin of the glucagon superfamily, we isolated and sequenced the complementary DNA and partial gene that encode pituitary adenylate cyclase-activating polypeptide (PACAP) from a protochordate (tunicate), a sister group of the amphioxus and vertebrates, but one that evolved before the amphioxus. This is the first report of any superfamily member sequenced from an invertebrate. Transcription of the tunicate pacap1 gene results in a messenger RNA that is 507 bp. The gene contains 3 exons that encode a signal peptide, GRF-like peptide(1-27), and PACAP(1-27). The tunicate GRF-like peptide has 59% identity with human GRF, whereas the deduced amino acids of tunicate PACAP(1-27) have 96% identity with the ovine, human, and salmon PACAP(1-27) forms. Another complementary DNA clone pacap2 was isolated and shown to contain 4 exons that encode a signal peptide, a cryptic peptide, and two peptides that are clearly members of the glucagon superfamily. One of the peptides has 89% sequence identity to the tunicate PACAP encoded in pacap1. A comparison of the two structurally related PACAP clones, each encoding two peptides on separate exons, shows high inter- and intraexon nucleotide sequence identity. Sequence analysis suggests that an exon duplication followed by a gene duplication was responsible for the origin of the two genes. It is argued that the PACAP gene is derived from the protochordate ancestral genes that led to the vertebrate forms of GRF and PACAP.
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PMID:Two protochordate genes encode pituitary adenylate cyclase-activating polypeptide and related family members. 916 26

Growth hormone-releasing hormone (GHRH) and pituitary adenylate cyclase-activating polypeptide (PACAP) are structurally and functionally related members of the glucagon superfamily, a group of hormones important in development, growth, and metabolism. Our objectives were to determine the developmental expression pattern of the ghrh-pacap1 gene using the zebrafish model. The temporal and spatial expression pattern of the ghrh-pacap1 gene was examined by RT-PCR and in situ hybridization. In zebrafish, the ghrh-pacap1 mRNA transcript was expressed throughout development beginning at the transition between the blastula and gastrula periods. During midgastrulation, alternative splicing resulted in the generation of a novel transcript lacking the cryptic peptide. During the segmentation period, expression was localized to the neural tube, developing eye, and neural crest; strong expression was found in the developing cerebellum. Later in development, expression was localized in the hatching gland and developing pharyngeal arches. The temporal and spatial expression pattern of the ghrh-pacap1 transcript suggests that these hormones may modulate patterning during development.
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PMID:Developmental changes in the expression of growth hormone-releasing hormone and pituitary adenylate cyclase-activating polypeptide in zebrafish. 1248 90

Dipeptidyl peptidase 4 (DPP4) is an exopeptidase found either on cell surfaces where it is highly regulated in terms of its expression and surface availability (CD26) or in a free/circulating soluble constitutively available and intrinsically active form. It is responsible for proteolytic cleavage of many peptide substrates. In this review we discuss the idea that DPP4-cleaved peptides are not necessarily inactivated, but rather can possess either a modified receptor selectivity, modified bioactivity, new antagonistic activity, or even a novel activity relative to the intact parent ligand. We examine in detail five different major DPP4 substrates: glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), peptide tyrosine-tyrosine (PYY), and neuropeptide Y (NPY), and stromal derived factor 1 (SDF-1 aka CXCL12). We note that discussion of the cleaved forms of these five peptides are underrepresented in the research literature, and are both poorly investigated and poorly understood, representing a serious research literature gap. We believe they are understudied and misinterpreted as inactive due to several factors. This includes lack of accurate and specific quantification methods, sample collection techniques that are inherently inaccurate and inappropriate, and a general perception that DPP4 cleavage inactivates its ligand substrates. Increasing evidence points towards many DPP4-cleaved ligands having their own bioactivity. For example, GLP-1 can work through a different receptor than GLP-1R, DPP4-cleaved GIP can function as a GIP receptor antagonist at high doses, and DPP4-cleaved PYY, NPY, and CXCL12 can have different receptor selectivity, or can bind novel, previously unrecognized receptors to their intact ligands, resulting in altered signaling and functionality. We believe that more rigorous research in this area could lead to a better understanding of DPP4's role and the biological importance of the generation of novel cryptic ligands. This will also significantly impact our understanding of the clinical effects and side effects of DPP4-inhibitors as a class of anti-diabetic drugs that potentially have an expanding clinical relevance. This will be specifically relevant in targeting DPP4 substrate ligands involved in a variety of other major clinical acute and chronic injury/disease areas including inflammation, immunology, cardiology, stroke, musculoskeletal disease and injury, as well as cancer biology and tissue maintenance in aging.
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PMID:What doesn't kill you makes you stranger: Dipeptidyl peptidase-4 (CD26) proteolysis differentially modulates the activity of many peptide hormones and cytokines generating novel cryptic bioactive ligands. 3075 73