Ileal expression of gastrin and cholecystokinin

Friis‐Hansen, Lennart; Rehfeld, Jens F.

doi:10.1016/0014-5793(94)80301-3

Cited by 16 publications

(9 citation statements)

References 34 publications

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“…Our transfection studies indicate that relatively profound changes in charge distribution and structure around the sulfation site do not affect sulfation dramatically. Nevertheless, eutopically expressed gastrin is completely nonsulfated in pituitary corticotrophs (42,43) and in ileal mucosa cells (44). Moreover, antral gastrin is not sulfated either in the horse 2 or in the structurally more remote turtle gastrin (37), although both proteins are readily sulfated in HIT cells.…”

Section: Discussionmentioning

confidence: 98%

New Consensus Features for Tyrosine O-Sulfation Determined by Mutational Analysis

Bundgaard

Vuust²,

Rehfeld

1997

Journal of Biological Chemistry

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108

101

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Tyrosine sulfation is an ubiquitous modification of proteins synthesized along the secretory pathway. It enhances protein-protein interactions and may be necessary for the bioactivity of secreted proteins and peptides. To predict tyrosine sulfation, a consensus has been proposed based on sequence comparisons of known substrates and on in vitro studies using synthetic peptides. This consensus predicts the presence of acidic residues on the amino-terminal side of the target tyrosine as the key feature. Using site-directed mutagenesis, we have examined the role of residues neighboring the sulfation site of an intact protein, human progastrin, in vivo. The results show that the charge of the residue in the amino-terminal position (؊1) of the tyrosine is critical and can be neutral or acidic, whereas a basic residue abolishes sulfation. In addition, the degree of sulfation is influenced by the residues in positions ؊2 and ؊3. Hence, surprisingly a basic residue in position ؊2 enhances sulfation. Our data suggest a considerably broader range of substrates for the tyrosylprotein sulfotransferase than hitherto assumed and that the tyrosylprotein sulfotransferase is cell-specifically expressed.

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Section: Discussionmentioning

confidence: 98%

New Consensus Features for Tyrosine O-Sulfation Determined by Mutational Analysis

Bundgaard

Vuust²,

Rehfeld

1997

Journal of Biological Chemistry

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108

101

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“…The stomachs from overnight-fasted and anesthetized mice were collected, and whole-stomach gastrin was extracted as previously described (54). The plasma (20 μL) and stomach-extracted gastrins were measured by radioimmunoassay (EuroDiagnostic AB).…”

Section: Methodsmentioning

confidence: 99%

Calcium-sensing receptor is a physiologic multimodal chemosensor regulating gastric G-cell growth and gastrin secretion

Feng

Petersen²,

Coy³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

123

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The calcium-sensing receptor (CaR) is the major sensor and regulator of extracellular Ca 2+ , whose activity is allosterically regulated by amino acids and pH. Recently, CaR has been identified in the stomach and intestinal tract, where it has been proposed to function in a non-Ca 2+ homeostatic capacity. Luminal nutrients, such as Ca 2+ and amino acids, have been recognized for decades as potent stimulants for gastrin and acid secretion, although the molecular basis for their recognition remains unknown. The expression of CaR on gastrin-secreting G cells in the stomach and their shared activation by Ca 2+ , amino acids, and elevated pH suggest that CaR may function as the elusive physiologic sensor regulating gastrin and acid secretion. The genetic and pharmacologic studies presented here comparing CaR-null mice and wild-type littermates support this hypothesis. Gavage of Ca 2+ , peptone, phenylalanine, Hepes buffer (pH 7.4), and CaR-specific calcimimetic, cinacalcet, stimulated gastrin and acid secretion, whereas the calcilytic, NPS 2143, inhibited secretion only in the wild-type mouse. Consistent with known growth and developmental functions of CaR, G-cell number was progressively reduced between 30 and 90 d of age by more than 65% in CaR-null mice. These studies of nutrient-regulated G-cell gastrin secretion and growth provide definitive evidence that CaR functions as a physiologically relevant multimodal sensor. Medicinals targeting diseases of Ca 2+ homeostasis should be reviewed for effects outside traditional Ca 2+ -regulating tissues in view of the broader distribution and function of CaR.

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“…(Hortin et al, 1986;Huttner and Baeuerle, 1988;Niehrs et al, 1994 (Andersen, 1985). Complete lack of sulfation is found in the adenohypophysis (Rehfeld and Larsson, 1981) and in the ileum (Friis-Hansen and Rehfeld, 1994). In contrast, gastrin is completely sulfated in the fetal pancreas (Brand et al, 1984).…”

Section: Discussionmentioning

confidence: 99%

“…Additional functions in progastrin maturation have been suggested earlier. Thus, examinations of plasma and tissue samples from hypergastrinaemic patients showed a direct correlation between the degree of sulfation and the maturation of progastrin to gastrin-17 (Andersen and Stadil, 1983;Jensen et al, 1989 Rehfeld, 1994).…”

Section: Discussionmentioning

confidence: 99%

Tyrosine O-sulfation promotes proteolytic processing of progastrin.

1995

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1Tyrosine 0-sulfation is a common post-translational modification of secretory and membrane proteins. The biological function of sulfation is known in only a few proteins, where it appears to enhance protein-protein interactions. Based on known sequences around sulfated tyrosines, a consensus sequence for prediction of target tyrosines has been proposed. However, some proteins are tyrosine sulfated at sites that deviate from the proposed consensus. Among these is progastrin. It is possible that the deviation explains the incomplete sulfation characteristic for bioactive gastrin peptides. In order to test this hypothesis, we have performed site-directed mutagenesis of the gastrin gene followed by heterologous expression in an endocrine cell line. The results show that substitution of the alanyl residue immediately N-terminal to the sulfated tyrosine with an acidic amino acid promotes the sulfation of gastrin peptides. Hence, the study supports the proposed consensus sequence for tyrosine sulfation. Importantly, however, the results also reveal that complete sulfation increases the endoproteolytic maturation of progastrin. Thus, our study suggests an additional function for tyrosine sulfation of possible general significance.

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Ileal expression of gastrin and cholecystokinin

Cited by 16 publications

References 34 publications

New Consensus Features for Tyrosine O-Sulfation Determined by Mutational Analysis

New Consensus Features for Tyrosine O-Sulfation Determined by Mutational Analysis

Calcium-sensing receptor is a physiologic multimodal chemosensor regulating gastric G-cell growth and gastrin secretion

Tyrosine O-sulfation promotes proteolytic processing of progastrin.

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