Pancreastatin molecular forms in normal human plasma

Kitayama, Noboru; Tateishi, Kensuke; Funakoshi, Akihiro; Miyasaka, Kyoko; Shimazoe, Takao; Kono, Akira; Iwamoto, Naoko; Matsuoka, Yuji

doi:10.1016/0024-3205(94)90028-0

Cited by 18 publications

(5 citation statements)

References 14 publications

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“…PST, a C-terminally glycine-amidated 49-mer peptide, was identified in 1986 as a potent inhibitor of glucose-stimulated insulin secretion (GSIS) ( 32 ). Two molecular forms were detected in human plasma: a 52 amino acid form (CgA 250–301 ) and a larger form with a molecular weight of 15–21 kDa ( 65 ). Although the PST sequence is well conserved in mammals, showing 41.5% homology between humans and the Tasmanian devil, no homology could be detected in submammalian vertebrates (Figure 1 B) ( 66 – 68 ).…”

Section: Pst Inhibits Glucose-stimulated Insulin Secretion (Gsis)mentioning

confidence: 99%

Chromogranin A Regulation of Obesity and Peripheral Insulin Sensitivity

Bandyopadhyay

Mahata

2017

Front. Endocrinol.

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Chromogranin A (CgA) is a prohormone and granulogenic factor in endocrine and neuroendocrine tissues, as well as in neurons, and has a regulated secretory pathway. The intracellular functions of CgA include the initiation and regulation of dense-core granule biogenesis and sequestration of hormones in neuroendocrine cells. This protein is co-stored and co-released with secreted hormones. The extracellular functions of CgA include the generation of bioactive peptides, such as pancreastatin (PST), vasostatin, WE14, catestatin (CST), and serpinin. CgA knockout mice (Chga-KO) display: (i) hypertension with increased plasma catecholamines, (ii) obesity, (iii) improved hepatic insulin sensitivity, and (iv) muscle insulin resistance. These findings suggest that individual CgA-derived peptides may regulate different physiological functions. Indeed, additional studies have revealed that the pro-inflammatory PST influences insulin sensitivity and glucose tolerance, whereas CST alleviates adiposity and hypertension. This review will focus on the different metabolic roles of PST and CST peptides in insulin-sensitive and insulin-resistant models, and their potential use as therapeutic targets.

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Section: Pst Inhibits Glucose-stimulated Insulin Secretion (Gsis)mentioning

confidence: 99%

Chromogranin A Regulation of Obesity and Peripheral Insulin Sensitivity

Bandyopadhyay

Mahata

2017

Front. Endocrinol.

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“…Several processing intermediates have been reported for PST in cells or tissues, and all contained the biologically conserved active carboxyl-terminal part of the molecule [2]–[5]. The amidated carboxyl terminus of PST is a feature in common with many neuropeptides and gastrointestinal hormones such as NPY and PYY.…”

Section: Introductionmentioning

confidence: 99%

Discovery of a Novel Target for the Dysglycemic Chromogranin A Fragment Pancreastatin: Interaction with the Chaperone GRP78 to Influence Metabolism

et al. 2014

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RationaleThe chromogranin A-derived peptide pancreastatin (PST) is a dysglycemic, counter-regulatory peptide for insulin action, especially in liver. Although previous evidence for a PST binding protein has been reported, such a receptor has not been identified or sequenced.Methods and ResultsWe used ligand affinity to purify the PST target, with biotinylated human PST (hCHGA273–301-amide) as “bait” and mouse liver homogenate as “prey”, and identified GRP78 (a.k.a. “78 kDa Glucose Regulated Protein”, HSPA5, BIP) as a major interacting partner of PST. GRP78 belongs to the family of heat shock proteins (chaperones), involved in several cellular processes including protein folding and glucose metabolism. We analyzed expression of GRP78 in the absence of PST in a mouse knockout model lacking its precursor CHGA: hepatic transcriptome data revealed global over-expression of not only GRP78 but also other heat shock transcripts (of the “adaptive UPR”) in CHGA(−/−) mice compared to wild-type (+/+). By contrast, we found a global decline in expression of hepatic pro-apoptotic transcripts in CHGA(−/−) mice. GRP78's ATPase enzymatic activity was dose-dependently inhibited by PST (IC50∼5.2 µM). PST also inhibited the up-regulation of GRP78 expression during UPR activation (by tunicamycin) in hepatocytes. PST inhibited insulin-stimulated glucose uptake in adipocytes, and increased hepatic expression of G6Pase (the final step in gluconeogenesis/glycogenolysis). In hepatocytes not only PST but also other GRP78-ATPase inhibitors (VER-155008 or ADP) increased G6Pase expression. GRP78 over-expression inhibited G6Pase expression in hepatocytes, with partial restoration by GRP78-ATPase inhibitors PST, VER-155008, or ADP.ConclusionsOur results indicate that an unexpected major hepatic target of PST is the adaptive UPR chaperone GRP78. PST not only binds to GRP78 (in pH-dependent fashion), but also inhibits GRP78's ATPase enzymatic activity, and impairs its biosynthetic response to UPR activation. PST decreases insulin-stimulated cellular glucose uptake, and PST as well as other chaperone ATPase activity inhibitors augment expression of G6Pase; GRP78 over-expression antagonizes this PST action. Analysis of the novel PST/GRP78 interaction may provide a new avenue of investigation into cellular glycemic control as well as dysglycemia.

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“…Using a C-terminal specific porcine antibody to isolate PST from tumors and blood of patients with insulinoma, three different forms of PST were isolated: PST 186 (hCgA 116-301 ), PST 92 (hCgA 210-301 ), and PST 48 (hCgA 254-301 ) [69,70]. Similarly, using a radioimmunoassay sensitive to the C-terminal glycine amide of human PST, different molecular sizes of PST were isolated from the serum of healthy donors, which were analyzed by high-performance liquid chromatography [71]. All of these forms of PST have the same C-terminus indicating high conservation between species and that the C-terminus is functionally important.…”

Section: Biological Features Of Pstmentioning

confidence: 99%

“…The different forms of PST that are reported in humans developed through various proteolytic cleavage sites [69][70][71]. Following cleavage, exoproteases might also remove single basic residues at the termini of the peptide fragments.…”

Section: Processing Of Pstmentioning

confidence: 99%