Relaxant effect of xenin on rat ileum is mediated by apamin-sensitive neurotensin-type receptors

Clemens, Andreas; Katsoulis, Stavros; Nustede, R.; Seebeck, Jörg; Seyfarth, K.; Morys-Wortmann, Corinna; Feurle, Gerhard E.; Fölsch, Ulrich R.; Schmidt, Wolfgang E.

doi:10.1152/ajpgi.1997.272.1.g190

Cited by 17 publications

(30 citation statements)

References 12 publications

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“…Interestingly, basal Xenin-25 increases cytosolic free calcium levels by binding to neurotensin receptor-1. Genetic and pharmacological data suggest that the effects of Xen are mediated by neurotensin receptor-1 (NTSR1) (7,15,16,28,46,47). The percentage of MENs excited by neurotensin (9.3% of 486) was similar (P ϭ 0.68) to that excited by Xen (Table 1).…”

Section: Isolatedmentioning

confidence: 81%

Xenin-25 increases cytosolic free calcium levels and acetylcholine release from a subset of myenteric neurons

Zhang

Hyrc

Wang³

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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Xenin-25 (Xen) is a 25 amino acid neurotensin-related peptide reportedly produced with glucose-dependent insulinotropic polypeptide (GIP) by a subset of K cells in the proximal gut. We previously showed exogenously administered Xen, with GIP but not alone, increases insulin secretion in humans and mice. In mice, this effect is indirectly mediated via a central nervous system-independent cholinergic relay in the periphery. Xen also delays gastric emptying, reduces food intake, induces gall bladder contractions, and increases gut motility and secretion from the exocrine pancreas, suggesting that some effects of Xen could be mediated by myenteric neurons (MENs). To determine whether Xen activates these neurons, MENs were isolated from guinea pig proximal small intestines. Cells expressed neuronal markers and exhibited typical neuron-like morphology with extensive outgrowths emanating from cell bodies. Cytosolic free Ca(2+) levels ([Ca(2+)](i)) were measured using Fura-2. ATP/UTP, KCl, and forskolin increased [Ca(2+)](i) in 99.6%, 92%, and 23% of the MENs imaged, respectively, indicating that they are functional and activated by nucleotide receptor signaling, direct depolarization, and cAMP. [Ca(2+)](i) increased in only 12.7% of MENs treated with Xen. This rise was blocked by pretreatment with EGTA, diazoxide, SR48692, and neurotensin. Thus the Xen-mediated increase in [Ca(2+)](i) involves influx of extracellular Ca(2+) and activation of neurotensin receptor-1 (NTSR1). Xen also increased acetylcholine release from MENs. Amylin, produced by β-and enteroendocrine cells, delays gastric emptying and increased [Ca(2+)](i) almost exclusively in Xen-responsive MENs. Immunohistochemistry demonstrated NTSR1 expression in human duodenal MENs. Thus myenteric rather than central neurons could mediate some effects of Xen and amylin.

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Section: Isolatedmentioning

confidence: 81%

Xenin-25 increases cytosolic free calcium levels and acetylcholine release from a subset of myenteric neurons

Zhang

Hyrc

Wang³

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…6C). Xenopsin shows strong structural and functional similarities to the hormones neurotensin (NT) and xenopsin-related peptide 2 (XRP-2), two universal NT receptor agonists in vertebrates [26], [64], [65]. These hormones share five and six C-terminal AAs with xenopsin, respectively, all of which are involved in neurotensin receptor binding [65].…”

Section: Discussionmentioning

confidence: 99%

Origin and Functional Diversification of an Amphibian Defense Peptide Arsenal

Roelants

Fry

et al. 2013

PLoS Genet

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The skin secretion of many amphibians contains an arsenal of bioactive molecules, including hormone-like peptides (HLPs) acting as defense toxins against predators, and antimicrobial peptides (AMPs) providing protection against infectious microorganisms. Several amphibian taxa seem to have independently acquired the genes to produce skin-secreted peptide arsenals, but it remains unknown how these originated from a non-defensive ancestral gene and evolved diverse defense functions against predators and pathogens. We conducted transcriptome, genome, peptidome and phylogenetic analyses to chart the full gene repertoire underlying the defense peptide arsenal of the frog Silurana tropicalis and reconstruct its evolutionary history. Our study uncovers a cluster of 13 transcriptionally active genes, together encoding up to 19 peptides, including diverse HLP homologues and AMPs. This gene cluster arose from a duplicated gastrointestinal hormone gene that attained a HLP-like defense function after major remodeling of its promoter region. Instead, new defense functions, including antimicrobial activity, arose by mutation of the precursor proteins, resulting in the proteolytic processing of secondary peptides alongside the original ones.Although gene duplication did not trigger functional innovation, it may have subsequently facilitated the convergent loss of the original function in multiple gene lineages (subfunctionalization), completing their transformation from HLP gene to AMP gene. The processing of multiple peptides from a single precursor entails a mechanism through which peptide-encoding genes may establish new functions without the need for gene duplication to avoid adaptive conflicts with older ones.

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“…Given that xenin-mediated effects are thought to stem, in part, from binding and activating the neurotensin receptor (Clemens et al 1997) involving calcium-dependent potassium channels , we thought it prudent to investigate the mechanism of xenin-induced insulin release observed. However, no significant changes in membrane potential or intra-cellular Ca 2C were observed even with the highest concentration of xenin (10 K6 M) tested under normo-or hyperglycaemic conditions.…”

Section: Discussionmentioning

confidence: 99%

“…Despite this, its exact role in mammalian physiology remains elusive. Since xenin is structurally similar to neurotensin, it is thought to bind and activate the neurotensin receptor subtype 1 (Clemens et al 1997). Interestingly, the feedingsuppressive effect of xenin is abolished in neurotensin receptor-deficient mice, thus supporting a role for this receptor in the anorectic effect of xenin (Kim & Mizuno 2010).…”

Section: Introductionmentioning

confidence: 96%

Evaluation of the degradation and metabolic effects of the gut peptide xenin on insulin secretion, glycaemic control and satiety

Taylor

Irwin²,

McKillop³

et al. 2010

Journal of Endocrinology

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Recently, glucagon-like peptide 1 (GLP1) and glucosedependent insulinotropic polypeptide (GIP) have received much attention regarding possible roles in aetiology and treatment of type 2 diabetes. However, peptides co-secreted from the same enteroendocrine cells are less well studied. The present investigation was designed to characterise the in vitro and in vivo effects of xenin, a peptide co-secreted with GIP from intestinal K-cells. We examined the enzymatic stability, insulin-releasing activity and associated cAMP production capability of xenin in vitro. In addition, the effects of xenin on satiety, glucose homoeostasis and insulin secretion were examined in vivo. Xenin was time dependently degraded (t 1/2 Z162G6 min) in plasma in vitro. In clonal BRIN-BD11 cells, xenin stimulated insulin secretion at 5 . 6 mM (P!0 . 05) and 16 . 7 mM (P!0 . 05 to P!0 . 001) glucose levels compared to respective controls. Xenin also exerted an additive effect on GIP, GLP1 and neurotensin-mediated insulin secretion. In clonal b-cells, xenin did not stimulate cellular cAMP production, alter membrane potential or elevate intra-cellular Ca 2C. In normal mice, xenin exhibited a short-acting (P!0 . 01) satiety effect at high dosage (500 nmol/kg). In overnight fasted mice, acute injection of xenin enhanced glucose-lowering and elevated insulin secretion when injected concomitantly or 30 min before glucose. These effects were not observed when xenin was administered 60 min before the glucose challenge, reflecting the short half-life of the native peptide in vivo. Overall, these data demonstrate that xenin may have significant metabolic effects on glucose control, which merit further study.

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Relaxant effect of xenin on rat ileum is mediated by apamin-sensitive neurotensin-type receptors

Cited by 17 publications

References 12 publications

Xenin-25 increases cytosolic free calcium levels and acetylcholine release from a subset of myenteric neurons

Xenin-25 increases cytosolic free calcium levels and acetylcholine release from a subset of myenteric neurons

Origin and Functional Diversification of an Amphibian Defense Peptide Arsenal

Evaluation of the degradation and metabolic effects of the gut peptide xenin on insulin secretion, glycaemic control and satiety

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