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Peptide YY (PYY) and neuropeptide Y (NPY) activate Y receptors, targets under consideration as treatments for diarrhoea and other intestinal disorders. We investigated the gastrointestinal consequences of selective PYY or NPY ablation on mucosal ion transport, smooth muscle activity and transit using wild-type, single and double peptide knockout mice, comparing mucosal responses with those from human colon.
1. This study investigated the effects of BIIE0246, a novel neuropeptide Y (NPY) Y2 receptor antagonist, on the inhibition of cholinergic neuroeffector transmission in rat heart and guinea-pig trachea and purinergic neuroeffector transmission in guinea-pig vas deferens produced by the NPY Y2 receptor agonist, N-acetyl [Leu28,31] NPY 24-36. 2. In pentobarbitone anaesthetized rats, supramaximal stimulation every 30 s, of the vagus nerve innervating the heart, increased pulse interval by approximately 100 ms. This response was attenuated by intravenous administration of N-acetyl [Leu28,31] NPY 24-36 (10 nmol x kg(-1)). 3. Transmural stimulation of segments of guinea-pig trachea at 1 min intervals with 5 s trains of stimuli at 0.5, 5, 10, 20 and 40 Hz evoked contractions which were reduced in force by N-acetyl [Leu28,31] NPY 24-36 (2 microM). 4. In guinea-pig vasa deferentia, the amplitude of excitatory junction potentials evoked by trains of 20 stimuli at 1 Hz was reduced in the presence of N-acetyl [Leu28,31] NPY 24-36 (1 microM). 5. In all preparations BIIE0246 attenuated the inhibitory effect of N-acetyl [Leu28,31] NPY 24-36 but had no effect when applied alone. 6. The findings support the view that the nerve terminals of postganglionic parasympathetic and sympathetic neurones possess neuropeptide Y Y2 receptors which, when activated, reduce neurotransmitter release.
Although previous studies have demonstrated that neuropeptide Y (NPY) modulates nociceptors, the relative contributions of the Y1 and Y2 receptors are unknown. Therefore, we evaluated the effect of Y1 and Y2 receptor activation on nociceptors stimulated by bradykinin (BK) and prostaglandin E2 (PGE2).
Neuropeptide Y (NPY) and its receptors have been implicated in the control of emotional-affective processing, but the mechanism is unclear. While it is increasingly evident that stimulation of Y₁ and inhibition of Y₂ receptors produce prominent anxiolytic and antidepressant effects, the contribution of the individual NPY receptor subtypes in the acquisition and extinction of learned fear are unknown.
(1) This study investigated the effects of galanin (GAL) on inhibition of cholinergic (vagal) activity in the mouse heart using control galanin knockout (GAL-KO) and GAL-1R receptor knockout (GAL-1R-KO) mice. (2) In pentobarbitone anaesthetised mice, supramaximal stimulation every 30 s of the vagus nerve innervating the heart, increased pulse interval (PI) by approximately 50 ms or decreased heart rate by approximately 100 beats min-1. This response was attenuated by intravenous administration of GAL (dose ranged from 0.8 to 13 nmol kg-1) in a dose-dependent manner. (3) In GAL-KO mice, the magnitude of inhibition of the increase in PI (DeltaPI) following a bolus dose of GAL was not different from the DeltaPI in control mice, and neuropeptide Y (NPY), previously shown to attenuate vagal inhibitory activity in mice, evoked a comparative inhibition of DeltaPI in GAL-KO mice. (4) In GAL-1R-KO mice, an intravenous, bolus injection of GAL had no inhibitory effect on vagal activity. (5) In control mice, stimulation of the sympathetic nerve at 25 V, 10 Hz for 2 min in the presence of propranolol evoked a long-lasting attenuation of DeltaPI. The inhibitory effect on DeltaPI was reduced in the presence of the NPY Y2 antagonist, BIIE0246. (6) In GAL-1R-KO mice, stimulation of the sympathetic nerve in the presence of propranolol evoked an attenuation of DeltaPI not significantly different from the response in control mice in the presence of BIIE0246. Following administration of BIIE0246 in GAL-1R-KO mice, the inhibition of DeltaPI that followed stimulation of the sympathetic nerve was abolished. (7) These findings support the view that the nerve terminals of parasympathetic neurons in the mouse heart possess both GAL-1R and NPY Y2 receptors which, when activated, reduce acetylcholine release.
beta-Arrestins are critical scaffold proteins that shape spatiotemporal signalling from seven transmembrane domain receptors (7TMRs). Here, we study the association between neuropeptide Y (NPY) receptors and beta-arrestin2, using bimolecular fluorescence complementation (BiFC) to directly report underlying protein-protein interactions.
1 Neuropeptide Y (NPY) and NPY receptors are most abundant in the hippocampal formation where they modulate cognitive functions. Expression of NPY receptors in rat cultured primary hippocampal cells was investigated in the present study by use of combined molecular, pharmacological and immunohistochemical approaches, including the cloning of the rat Y2 receptor described here for the first time. 2 More than 70% of the hippocampal neurones were endowed with [125I]-[Leu31,Pro34]PYY Y1-like receptor silver grain accumulations and Y1 receptor immunostaining. These radio- and immuno-labelling signals were distributed over cell bodies and processes of bipolar, stellate and pyramidal-like neuronal cells, as confirmed by neurone-specific enolase and MAP-2 staining. 3 Competition binding profiles revealed that specific [125I]-[Leu31,Pro34]PYY binding was competitively displaced according to a ligand selectivity pattern prototypical of the Y1 receptor sub-type with [Leu31,Pro34]substituted NPY/PYY analogues >> C-terminal fragments = pancreatic polypeptides, with the non-peptide antagonist BIBP3226 being most potent. This profile excludes the possible labelling by [125I]-[Leu31,Pro34]PYY of the newly cloned Y4, Y5 and Y6 receptors. 4 The expression of the genuine Y1 receptor was confirmed by RT-PCR in hippocampal cultures. In contrast, negligible levels of Y2-like/[125I]-PYY3-36 binding were detected in these cultures in spite of the presence of its mRNA, as characterized by RT-PCR. The expression of both the Y1 and the Y2 receptor mRNAs was also noted in normal embryonic hippocampal tissues showing that signals expressed in cultured neurones were also present in utero. 5 Taken together, these results suggest that the Y1 receptor subtype may be of critical importance in the normal functioning of the rat hippocampus, especially during brain development and maturation.
1. The effects of peptide YY (PYY), neuropeptide Y (NPY) and structurally related peptides upon field stimulation-induced and phenylephrine-mediated contractile responses in the cauda epididymis of the guinea-pig were investigated. 2. Preparations of cauda epididymis responded to field stimulation with contractions which were completely attenuated by both the neurotoxin, tetrodotoxin (500 nM), and also by the alpha-adrenoceptor antagonist, phentolamine (3 microM). PYY (n=7) and the truncated peptide analogue PYY(3-36) (n=5) inhibited field stimulation-induced contractions (pIC50+s.e.mean: 8.9+/-0.2 and 9.4+/-0.2, respectively). Pancreatic polypeptide (PP, up to 1 microM, n=6), NPY (up to 100 nM, n=6) and the NPY analogues [Leu31,Pro34]NPY (n=6) and NPY(13-36) (both up to 1 microM, n=5) had no significant effect. 3. The NPY Y1 receptor antagonist BIBP3226 ((R)-N2-(diphenylacetyl)-N[(4-hydroxyphenyl)-methyl]-argininami de) at 750 nM (n=6) and 7.5 microM (n=6) did not affect the PYY-mediated inhibition of field stimulation-induced contractions (pIC50 8.9+/-0.3 and 9.0+/-0.3, respectively). In the presence of BIBP3226 (7.5 microM), NPY (n=6) inhibited field stimulation-induced contractions (pIC50 8.0+/-0.2). 4. NPY, PYY and PYY(3-36) inhibited [3H]-noradrenaline release from preparations of epididymis (pIC50 values 7.9+/-0.7, 9.6+/-0.8 and 10.0+/-0.9, respectively, all n=6). The agonists PP and [Leu31,Pro34]PYY (both up to 100 nM) were without significant effect (both n=6). 5. In preparations of cauda epididymis, stimulated with threshold concentrations of the alpha1-adrenoceptor agonist, phenylephrine (1 microM), both NPY (n=6) and PYY (n=7) elicited concentration-dependent increases in contractile force (with pEC50 values of 8.9+/-0.2 and 8.6+/-0.1, respectively). The effects of both NPY (n=6) and PYY (n=6) were antagonized by preincubation with BIBP3226 (75 nM; apparent pK(B)+/-s.e. values 8.3+/-1.0 and 8.2+/-0.6, respectively). The peptide analogues NPY(13-36) (n=5), PYY(3-36) (n=7) and [Leu31,Pro34]NPY (n=5) did not significantly augment responses to threshold concentrations of phenylephrine. 6. These results are consistent with the proposal that distinct NPY receptors mediate the (prejunctional) inhibition of field stimulation-induced contractions and the (postjunctional) potentiation of responses to phenylephrine in the cauda epididymis of the guinea-pig. The rank order of agonist potency (NPY > or = PYY >> NPY(13-36), [Leu31,Pro34]NPY and PYY(3-36) and the high potency of BIBP3226 indicate that the postjunctional receptor may be Y1-like. The rank orders of agonist potency in inhibiting field stimulation-induced contractile responses and [3H]-noradrenaline release (PYY(3-36) > or = PYY > NPY >> PP, NPY(13-36), [Leu31,Pro34]NPY and PYY(3-36) > or = PYY > NPY >> PP, [Leu31,Pro34]PYY, respectively) are consistent with the action of these peptides at a PYY-preferring receptor subtype, which may be distinct from the presently characterized NPY receptor subtypes.
Psychological stress exacerbates symptoms of urinary bladder dysfunction; however, the underlying brain mechanisms are unclear. We have demonstrated that centrally administered bombesin, a stress-related neuropeptide, facilitates the rat micturition reflex. Brain bombesin-like peptides modulate the serotoninergic nervous system activity under stress conditions; therefore, we examined whether brain 5-HT is involved in the bombesin-induced increased frequency of urination in urethane-anaesthetised male Sprague-Dawley rats.
1 Intracellular recording techniques were used to study neurotransmitter release mechanisms in postganglionic sympathetic nerve terminals in the guinea-pig isolated vas deferens. 2 Recently, a component of action potential-evoked release which is insensitive to high concentrations of the selective N-type calcium channel blocker omega-conotoxin GVIA termed 'residual release' has been described. Under these conditions, release of the neurotransmitter ATP evoked by trains of low frequency stimuli is abolished, but at higher frequencies a substantial component of release is revealed. 3 'Residual release' was studied with trains of 5 or 10 stimuli at stimulation frequencies of 10, 20 and 50 Hz. The alpha2-adrenoceptor agonist clonidine (30-100 nM) inhibited 'residual release', the degree of inhibition being most marked at the beginning of a train. 4 The alpha2-adrenoceptor antagonist yohimbine (1 microM) induced a marked increase in 'residual release' which was dependent on both the frequency of stimulation and the number of stimuli in a train. 5 Prostaglandin E2 (30 nM) and neuropeptide Y (100 nM) caused a rapid inhibition of 'residual release' at all stimulation frequencies examined. 6 4-Aminopyridine (100 microM) induced a powerful potential of 'residual release' and could reverse the inhibition of omega-conotoxin GVIA. 7 'Residual release' was modulated through presynaptic alpha2-adrenoceptors suggesting that (i) residual release of ATP is subject to alpha-autoinhibition through the co-release of noradrenaline, (ii) noradrenaline release can be triggered by calcium channels other than the N-type and (iii) when presynaptic receptors are activated, inhibition of transmitter release can occur by mechanisms other than modulation of calcium-entry through N-type calcium channels in postganglionic sympathetic nerves. Prostaglandin E2 and neuropeptide Y also modulated neurotransmitter release.
(1) We have investigated the properties of native and haemagglutinin (HA)-tagged neuropeptide Y (NPY) Y(1) receptors after mutation of the palmitoylation site Cys(337) to Ser or Ala. (2) In Chinese hamster ovary cells expressing similar receptor levels, the C337A mutation abolished incorporation of [(3)H]palmitic acid into the HA-Y(1) receptor. (3) Cys(337) substitution did not alter the affinities of Y(1) receptor agonists or antagonists, but it eliminated the ability of guanosine-5'-O-(3-thio)triphosphate (GTPgammaS) to displace [(125)I]PYY-specific binding (compared to approximately 50% inhibition in Y(1) or HA-Y(1) clones). (4) Stimulation of GTPgamma[(35)S] binding by native and HA-Y(1) receptors in standard incubation buffer (100 mM NaCl, 10 micro M GDP) was prevented by Cys(337) mutation. In this assay, the function of Y(1)(C337S) receptors could be partially rescued by reducing the Na(+) concentration, and when overexpressed (B(max): approximately 10 pmol mg(-1)), both HA-Y(1) and HA-Y(1)(C337A) receptors displayed similar responses to NPY and peptide YY (PYY). (5) In stably transfected adenocarcinoma cells expressing Y(1) or Y(1)(C337S) receptors, PYY inhibited anion secretion stimulated by vasoactive intestinal peptide (VIP; measured as short-circuit current, I(SC)) with similar potency (EC(50): 26-53 nM). In contrast to the transient Y(1) receptor-mediated responses observed at maximal PYY concentrations, I(SC) reductions in both Y(1)(C337S) clones were sustained. (6) We conclude that nonpalmitoylation of the Y(1) receptor reduces its coupling efficiency to G proteins, and may also indirectly influence desensitisation processes that depend on the formation of an active agonist-receptor conformation.
1. Neuropeptide Y (NPY) may inhibit sympathetic and vagal transmission via presynaptic Y2 receptors and cause vasoconstriction via postsynaptic Y1 receptors. We examined the effects of NPY and related peptides on cardiovascular parameters and autonomic reflexes in the conscious rabbit. Further, the postjunctional effects of NPY and related peptides were assessed on acetylcholine (ACh) and isoprenaline agonist dose-chronotropic response curves. 2. In conscious rabbits the cardiac baroreceptor-heart rate reflex (baroreflex), Bezold-Jarisch like and nasopharyngeal reflexes were assessed in control, propranolol-treated or methscopolamine-treated (baroreflex only) groups, before and 30 min after i.v. administration of NPY (10 microg kg[-1] + 5 microg kg[-1] min[-1]) or vehicle (saline, 10 ml h[-1]). The effects of equivalent pressor doses of [Leu31, Pro34]NPY or methoxamine on the baroreflex were also examined. In separate animals, dose-heart rate (HR) response curves to isoprenaline or ACh were constructed before and 15 min after administration of NPY, [Leu31,Pro34]NPY (ACh only) or [Leu31,Pro34]NpY + sodium nitroprusside (ACh only). 3. Administration of NPY-receptor agonists caused sustained bradycardia (in the absence of methscopolamine) and rightward shifts of the barocurves in all 3 groups. The range of sympathetically-mediated tachycardia was significantly decreased by NPY or [Leu31,Pro34]NPY in the methscopolamine-treated group. However, these changes in the baroreflex were no different from those elicted by equipressor doses of methoxamine. There was no vagal inhibition by any NPY-receptor agonist in all three autonomic reflexes examined. ACh or isoprenaline dose-HR response curves were not affected by NPY peptide administration. 4. We conclude that in the conscious rabbit, at a single dose that elicits a significant pressor response, exogenous NPY has no direct effect on modulation of cardiac and autonomic reflexes. Non-specific effects of exogenous NPY on the baroreflex may be fully explained by its pressor action. There was no effect of NPY on postjunctional ACh or isoprenaline agonist dose-response curves. Therefore, it is unlikely that endogenous NPY has a functional role in directly modulating cardiac autonomic neurotransmission in the rabbit.
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