Secretin and Cholecystokinin

Mutt, Viktor

doi:10.1016/b978-0-12-027311-9.50012-3

Cited by 16 publications

(5 citation statements)

References 423 publications

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“…However, it is, like the others, composed of 27-amino acid residues and is C-terminally amidated (9). The main action of secretin is to stimulate secretion of bicarbonate-rich pancreatic juice, but it also exerts other actions (10). Although secretin immunoreactivity, as well as bioactivity, has been reported in the central nervous system (11)(12)(13), secretin has so far only been isolated from intestine, where it is known to be localized in endocrine cells, called S cells, in the duodenum and upper jejunum (14,15).…”

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confidence: 99%

Processing of prosecretin: isolation of a secretin precursor from porcine intestine.

Gafvelin

Jörnvall²,

Mutt³

1990

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

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A precursor to the gastrointestinal hormone secretin has been isolated. The starting material for the purification of the precursor was a peptide fraction purified from pig intestinal extracts, containing peptides with a molecular weight higber than that of secretin. The purification could be followed by measurement ofsecretin bioactivity (alkali secreted in the pancreatic juice of anesthetized cat). Sequence analysis of the isolated secretin precursor revealed a 71-amino acid residue polypeptide that contained the sequence of secretin N terminally, followed by a Gly-Lys-Arg sequence and a Cterminal extension of 41-amino acid residues. With the exception of an arginine residue, which occurs directly after the Gly-Lys-Arg sequence, the remalnder of the C-terminal residues in this precursor are identical to the 40 C-terminal residues predicted by the recently described cDNA sequence for porcine preprosecretin. Compared to the deduced preprosecretin sequence, a stretch of 32 amino acid residues directly following the Gly-Lys-Arg sequence is missing in the now purified secretin precursor. This implies that differential splicing may occur when the secretin gene transcript is processed to mRNA.After its discovery in 1902 by Bayliss and Starling (1), almost 60 years elapsed before secretin (the porcine form of it) was isolated (2) and another 10 years elapsed before its primary structure was finally deduced (3). Pig secretin is a 27-amino acid residue peptide with a C-terminal valine amide. Cow and guinea pig secretin were found to be identical to that of the pig form (4, 46), whereas the human (5), dog (6), rat (7), and rabbit (8) secretin all differ slightly from each-other and from the porcine/bovine/guinea pig form. Chicken secretin is different from all the mammalian forms. However, it is, like the others, composed of 27-amino acid residues and is C-terminally amidated (9). The main action of secretin is to stimulate secretion of bicarbonate-rich pancreatic juice, but it also exerts other actions (10). Although secretin immunoreactivity, as well as bioactivity, has been reported in the central nervous system (11-13), secretin has so far only been isolated from intestine, where it is known to be localized in endocrine cells, called S cells, in the duodenum and upper jejunum (14,15).Until recently, the structure of the secretin precursor was unknown. This was probably due to secretin being composed of amino acids with degenerated codons, making it difficult to synthesize appropriate probes. However, using the polymerase chain reaction technique, Kopin et al.. (16) were able to isolate cDNA encoding pig and rat preprosecretin. The deduced amino acid sequence of the porcine secretin precursor (16) includes a signal peptide, an N-terminal flanking peptide ('10 amino acid residues), secretin, a Gly-Lys-Arg cleavage and amridation sequence, and a 72-amino acid residue C-terminal flanking peptide.Because of the difficulties in isolating the secretin precursor by conventional cDNA techniques and to investigate the ...

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confidence: 99%

Processing of prosecretin: isolation of a secretin precursor from porcine intestine.

Gafvelin

Jörnvall²,

Mutt³

1990

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

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“…Cholecystokinin (CCK) was originally described as a gastrointestinal peptide (for review, see Mutt, 1988) and later identified in the CNS (Vanderhaeghen et al, 1975), where it can be found in high concentrations in the cerebral cortex, hippocampus, amygdala, septum, and hypothalamus (Somogyi et al, 1984;Crawley, 1985;Nunzi et al, 1985;Sloviter and Nilaver, 1987). The synthesis of CCK in the brain occurs through the enzymatic cleavage of the propeptide CCK-33 to several biologically active forms, including the sulfated octapeptide (CCK-8S), which is the most prevalent (Rehfeld et al, 1985).…”

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Cholecystokinin Increases GABA Release by Inhibiting a Resting K⁺Conductance in Hippocampal Interneurons

Miller¹,

Hoffer²,

Svoboda³

et al. 1997

J. Neurosci.

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Cholecystokinin (CCK) is found co-localized with the inhibitory neurotransmitter GABA in interneurons of the hippocampus. Also, CCK receptors are found in abundance in this brain region. The possibility that CCK alters interneuron activity was examined using whole-cell current-and voltage-clamp recordings from visualized interneurons in the stratum radiatum of area CA1 in rat hippocampal slices. The effect of CCK on GABA-mediated IPSCs was also determined in pyramidal neurons. The sulfated octapeptide CCK-8S increased action potential frequency or generated inward currents in the majority of interneurons. These effects of CCK persisted in the presence of tetrodotoxin and cadmium, suggesting that they were direct. Current-voltage plots revealed that CCK-8S inhibited a conductance that was linear across command potentials and reversed near the equilibrium potential for K ϩ ions. The K ϩ channel blocker tetraethylammonium (10 mM) generated inward currents similar to those initiated by CCK, and it occluded the effect of the peptide. BaCl 2 (1 mM) and 4-aminopyridine (2 mM) did not alter the effect of CCK. The CCK B receptor antagonist PD-135,158 completely blocked the inward currents generated by CCK-8S. CCK also resulted in an increase in spontaneous action potential-dependent IPSC frequency, but no changes in action potential-independent miniature IPSCs or evoked IPSCs in pyramidal neurons. These results provide evidence that CCK can depolarize hippocampal interneurons through the inhibition of a resting K ϩ conductance, leading to increased tonic inhibition of pyramidal neurons. This action of CCK may contribute to its anticonvulsant properties, as observed in limbic seizure models.

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“…It is known to be produced in endocrine S cells of the small intestine (4,5), pancreatic 13 cells (6), and possibly also in brain (7,8). Its best known function is stimulation of the secretion of bicarbonaterich pancreatic fluid (9).…”

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Two alternative processing pathways for a preprohormone: a bioactive form of secretin.

Bonetto

Jörnvall

Mutt

et al. 1995

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

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An N-terminally 9-residue elongated form of secretin, secretin-(-9 to 27) amide, was isolated from porcine intestinal tissue and characterized. Current knowledge about peptide processing sites does not allow unambiguous prediction of the signal peptide cleavage site in preprosecretin but suggests cleavage in the region of residues -10 to -14 counted upstream from the N terminus of the hormone. However, the structure of the isolated peptide suggests that the cleavage between the signal peptide and the N-terminal propeptide occurs at the C-terminal side of residue -10. Moreover, the isolated peptide demonstrates that secretin can be fully processed C-terminally prior to the final N-terminal cleavage. The results from this report, and those from earlier studies, where C-terminally elongated variants were isolated, show that the processing of the secretin precursor may proceed by one of two alternative pathways, in which either of the two ends is processed first. The bioactivity of the N-terminally extended peptide on exocrine pancreatic secretion was lower than that of secretin, indicating the importance of the finally processed free N terminus of the hormone for interaction with secretin receptors.Secretin, a gastrointestinal hormone, was discovered by Bayliss and Starling in 1902 (1), isolated (2), and characterized as a 27-residue C-terminally amidated peptide (3). It is known to be produced in endocrine S cells of the small intestine (4, 5), pancreatic 13 cells (6), and possibly also in brain (7,8). Its best known function is stimulation of the secretion of bicarbonaterich pancreatic fluid (9).The structures of the rat and mouse secretin precursors as deduced from the corresponding cDNA sequences contain a signal sequence, an N-terminal flanking peptide, secretin, and a C-terminal extension peptide in that order (10, 11). The amino acid sequence of pig preprosecretin has also been so deduced, but it is probably lacking a few residues at the N terminus of the signal peptide (10). The amino acid sequence of the precursor is such that current knowledge about signal peptide cleavage sites (12) does not allow unambiguous prediction of this site. On the basis of the amino acid sequence, the cleavage of the signal peptide has been proposed to occur at the C-terminal side of any of the residues between -10 and -14 (10), most likely after residue -12, -13, or -14. Hence, for determination of the actual cleavage site, isolation of the corresponding N-terminally elongated form of secretin is necessary. In this report, we show that cleavage of the signal peptide probably occurs at the C-terminal side of residue -10, thus suggesting the position of cleavage and the length of the N-terminal flanking peptide.It has been shown earlier that other secretin proforms also exist in intestinal tissue. A proform, consisting of the secretin part together with its C-terminal flanking peptide, has been isolated, although the length of the latter was found to be 31 residues shorter than the amino acid sequence deduced fromThe pub...

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Secretin and Cholecystokinin

Cited by 16 publications

References 423 publications

Processing of prosecretin: isolation of a secretin precursor from porcine intestine.

Processing of prosecretin: isolation of a secretin precursor from porcine intestine.

Cholecystokinin Increases GABA Release by Inhibiting a Resting K⁺Conductance in Hippocampal Interneurons

Two alternative processing pathways for a preprohormone: a bioactive form of secretin.

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Secretin and Cholecystokinin

Cited by 16 publications

References 423 publications

Processing of prosecretin: isolation of a secretin precursor from porcine intestine.

Processing of prosecretin: isolation of a secretin precursor from porcine intestine.

Cholecystokinin Increases GABA Release by Inhibiting a Resting K+Conductance in Hippocampal Interneurons

Two alternative processing pathways for a preprohormone: a bioactive form of secretin.

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Cholecystokinin Increases GABA Release by Inhibiting a Resting K⁺Conductance in Hippocampal Interneurons