Actions of galanin fragments on rat, guinea-pig, and canine intestinal motility

Fox, J. E. T.; Brooks, Brad; McDonald, Thomas J.; Barnett, William; Kostolanska, F.; Yanaihara, Chizuko; Yanaihara, Noboru; Rökaeus, Åke

doi:10.1016/0196-9781(88)90105-2

Cited by 58 publications

(26 citation statements)

References 12 publications

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“…Studies with the C-terminal fragments [GAL- (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)] (20) and -(17-29) (G.F., unpublished data) showed no activity in the pancreas or the hippocampus, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…Previous studies carried out on intestinal smooth muscle showed the importance of the N-terminal portion of GAL for biological activity (18,19). Furthermore, N-terminal GAL fragments and analogs were able to mimic the effects of GAL on the pancreatic 83-cell line Rin m 5F, inhibiting forskolinstimulated cAMP production and insulin release (20).…”

Section: Introductionmentioning

confidence: 99%

“…A possible role for GAL as presynaptic modulator of the cholinergic function in the ventral hippocampus has been suggested by a recent electrophysiological study (14) and a behavioral study (15). Interactions between acetylcholine and GAL in the ventral hippocampus are not restricted to presynaptic sites but also involve actions that are considered postsynaptic (16) such as the GAL-mediated inhibition of the muscarinic agonist-stimulated breakdown of inositol phospholipids in the ventral hippocampus (17) and GAL inhibition of acetylcholine on a t-maze memory task in ventral forebrain lesioned rats (33).Previous studies carried out on intestinal smooth muscle showed the importance of the N-terminal portion of GAL for biological activity (18,19). Furthermore, N-terminal GAL fragments and analogs were able to mimic the effects of GAL on the pancreatic 83-cell line Rin m 5F, inhibiting forskolinstimulated cAMP production and insulin release (20).…”

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N-terminal galanin-(1-16) fragment is an agonist at the hippocampal galanin receptor.

Fisone

Berthold

Bedecs

et al. 1989

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

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The galanin N-terminal fragment [galanin-(1-16) The 29-amino-acid-long C-terminal amidated peptide galanin (GAL) (1) has been shown to be widely distributed in the central nervous system of mammals (2-6). GAL-like immunoreactivity has been localized, among other brain regions, in the septal area (4-8) where GAL coexists with acetylcholine in rat (7) and monkey (9) in a subpopulation of cholinergic cell bodies projecting to the hippocampus. and equilibrium binding studies with 1251I-labeled GAL (125I-GAL) have shown a high density of putative high-affinity GAL receptors in the ventral part of the hippocampus (13).In the ventral, but not in the dorsal, hippocampus GAL has been shown to inhibit, in a dose-dependent manner, the release of acetylcholine both in vitro and in vivo (12). A possible role for GAL as presynaptic modulator of the cholinergic function in the ventral hippocampus has been suggested by a recent electrophysiological study (14) and a behavioral study (15). Interactions between acetylcholine and GAL in the ventral hippocampus are not restricted to presynaptic sites but also involve actions that are considered postsynaptic (16) such as the GAL-mediated inhibition of the muscarinic agonist-stimulated breakdown of inositol phospholipids in the ventral hippocampus (17) and GAL inhibition of acetylcholine on a t-maze memory task in ventral forebrain lesioned rats (33).Previous studies carried out on intestinal smooth muscle showed the importance of the N-terminal portion of GAL for biological activity (18,19). Furthermore, N-terminal GAL fragments and analogs were able to mimic the effects of GAL on the pancreatic 83-cell line Rin m 5F, inhibiting forskolinstimulated cAMP production and insulin release (20).In this study, we focus our attention on the structureactivity relationship for the N terminus of GAL at receptors in the ventral hippocampus of the rat. Using equilibrium binding and autoradiographic techniques, we compare the synthetic N-terminal fragment GAL-(1-16) with rat GAL-(1-29) for its ability to displace 1251I-GAL from its receptors.GAL-(1-16) is also tested for its ability to inhibit the scopolamine-induced acetylcholine release in vivo and carbacholstimulated inositol phospholipid breakdown in a slice preparation from the rat ventral hippocampus. The importance of [Trp2] in the activity of the N-terminal fragment is examined.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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N-terminal galanin-(1-16) fragment is an agonist at the hippocampal galanin receptor.

Fisone

Berthold

Bedecs

et al. 1989

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

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“…The many published structure-activity studies on the effects of galanin fragments and analogues on the GAL-R1 (25)(26)(27)(28)(29)(30)(31) have demonstrated that the active receptor binding part of the peptide resides at the N-terminal portion of the peptide. The presence ofthe unmodified, first two N-terminal amino acid residues is particularly important for retention of high biological potency, since galanin 2-29 and 1-15 are nearly as potent biologically and at receptor displacement as the full 1-29, whereas 3-29, 10-29, and 20-29 are inactive.…”

Section: Discussionmentioning

confidence: 99%

Characterization of a high-affinity galanin receptor in the rat anterior pituitary: absence of biological effect and reduced membrane binding of the antagonist M15 differentiate it from the brain/gut receptor.

Wynick

Smith

Ghatei

et al. 1993

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

111

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Structure-activity studies demonstrate that galanin fragments 1-15 and 2-29 are fully active, whereas fragment 3-29 has been reported to be inactive, in a number of different in vivo models. M15, a chimeric peptide comprising galanin 1-13 and substance P 5-11, has recently been found to be a potent galanin antagonist. Galanin, a 29-amino acid peptide, was originally isolated from porcine intestine (1) and subsequently reported to be widely distributed in gut, pancreas, and the peripheral and central nervous systems (2, 3). Highest levels of galanin synthesis and storage occur within the hypothalamus in the median eminence (4), but it is also abundantly expressed in the anterior pituitary, where it has been shown to be estrogen inducible (5).Various studies have demonstrated effects of galanin on basal and stimulated release of prolactin (6, 7), growth hormone (8-11), and luteinizing hormone (12, 13) either from dispersed pituitary cells or at the hypothalamic level modulating dopamine, somatostatin (SRIF; somatotropin releaseinhibiting factor), and gonadotropin-releasing hormone (GnRH) release into the portal circulation. Recently galanin has been shown to be episodically released into the hypothalamo-pituitary portal circulation at concentrations in the nanomolar range (12), providing further evidence for its putative role as a modulator of pituitary function.In view of the high concentrations of galanin reaching or secreted by the anterior pituitary it is puzzling that a number of studies have failed to demonstrate anterior pituitary binding of [mono(125I)iodo-Tyr26]galanin (1251-Tyr-galanin) by membrane assay or by autoradiography in the rat or pig (14,15), although these studies demonstrated good thalamicand/or hypothalamic-specific galanin binding.Bartfai et al. (16) have recently synthesized a high-affinity galanin antagonist by fusing galanin 1-13 with substance P 5-11, which they termed M-15. This antagonist has been shown to be a potent inhibitor, at doses of 1 nM or less (with an IC50 of 0.1 nM), of the actions of galanin on the pancreas, smooth muscle, and hippocampus.The following studies demonstrate that galanin stimulates the release of prolactin from cultured anterior pituitary cells and that a specific galanin antiserum blocks basal prolactin secretion. The galanin antagonist M15 has no effect on basal or galanin-stimulated prolactin release. Using galanin 1251-labeled with the Bolton-Hunter (1251-BH) reagent at the N terminus, a single high-affinity galanin receptor in the pituitary is characterized. Unlike the brain/gut galanin receptor, the C-terminal part of the peptide is crucial for pituitary membrane binding. MATERIALS AND METHODSPituitary Dispersion. Anterior pituitaries were removed from randomly cycling female Wistar rats (Interfauna, Huntingdon, U.K.) immediately after death by decapitation and dispersed as described (17). Tissue was incubated while shaking at 37°C for 1 hr in Hanks' balanced salt solution (HBSS, GIBCO; containing 0.1% bovine serum albumin, pH 7.4) containing 0...

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“…Galanin receptors appear to recognize the N-terminal part of the galanin molecule (Ekblad et al, 1985;Fox et al, 1988;Murakami et al, 1989;Xu et al, 1989;Kuwahara et al, 1990). The rat vas deferens, thus, contains both inhibitory Y2 receptors and enhancing galanin receptors.…”

Section: Discussionmentioning

confidence: 99%

Functional effects and ligand binding of chimeric galanin‐neuropeptide Y (NPY) peptides on NPY and galanin receptor types

Kahl

Langel

Bartfai

et al. 1994

British J Pharmacology

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1 The effects and binding characteristics of a series of chimeric galanin-neuropeptide Y (NPY) peptides were examined in various preparations known to contain a predominant population of either Y1 or Y2 receptors for NPY or galanin receptors. 2 NPY suppressed the electrically stimulated twitches of the rat vas deferens (Y2 receptors), while galanin enhanced the electrically stimulated twitches. The galanin-NPY peptides M 32 (galanin(1-13)-NPY(25-36)), M69A (galanin(1-13)-Lys-[sNH-Gly-NPY(4-l)]NPY(25-36)) and M88 (galanin(1-12)-Ala-NPY(25-36)) evoked a concentration-dependent suppression of the electrically stimulated twitches. These chimeric peptides were about equipotent with NPY, while NPY (13-36) was about five times less potent than NPY itself. Also a stochiometric combination of the N-and C-terminal fragments NPY (1-24)NH2 and NPY (25-36) (each at 1 iM) was inactive in vas deferens. M120 (galanin (1-13)-NPY(14-36) (1 gLM) did not affect the NPY-mediated suppression of the stimulated twitches. 3 NPY evoked a concentration-dependent contraction in the guinea-pig isolated caval vein (Y1 receptors), while galanin (. 1 jIM) was inactive. M32, M69A and M88 induced a slight contraction at very high concentrations only (. 0.3 M), while M120 was inactive at 1 pM. None of the four chimeric peptides affected the contraction evoked by NPY. 4 Since the number of NPY receptors in the rat vas deferens and guinea-pig caval vein were too low, the affinities of the galanin-NPY peptides for [3H]-NPY binding sites were examined in membranes from rat brain areas known to contain predominant populations of Y1 receptors (cerebral cortex) and Y2 receptors (hippocampus), respectively. The chimeric peptides M32, M69A, M88, M120 and NPY (13-36) all had higher affinities for hippocampal binding sites than for cerebral cortical binding sites. These peptides were 90-440 times less potent than NPY at cerebral cortical binding sites and 15-125 times less potent than NPY at hippocampal binding sites. The most selective chimeric peptide was M32, which had a 20 fold higher affinity for hippocampal than for cerebral cortical binding sites.5 At hypothalamic [1251l-galanin binding sites M32, M88 and M69A were equipotent with galanin, while M120 was about 10 times less potent than galanin. M32, M88 and M69A, like galanin contracted the rat isolated jejunum. 6 The N-terminal portion (1-12) of galanin seems to permit a steric conformation of the attached NPY (25-36) part of the chimeric galanin-NPY peptides, which results in a facilitated Y2 but not Y1. receptor recognition and activation. None of the galanin-NPY peptides appeared to act as antagonists at either type of NPY receptor, probably due to their low affinity. Instead, they displayed a very high affinity for hypothalamic galanin receptors and probably act as galanin agonists in the rat jejunum.

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Actions of galanin fragments on rat, guinea-pig, and canine intestinal motility

Cited by 58 publications

References 12 publications

N-terminal galanin-(1-16) fragment is an agonist at the hippocampal galanin receptor.

N-terminal galanin-(1-16) fragment is an agonist at the hippocampal galanin receptor.

Characterization of a high-affinity galanin receptor in the rat anterior pituitary: absence of biological effect and reduced membrane binding of the antagonist M15 differentiate it from the brain/gut receptor.

Functional effects and ligand binding of chimeric galanin‐neuropeptide Y (NPY) peptides on NPY and galanin receptor types

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