Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Galanin, a 29-amino acid peptide, is uniquely distributed in human basal forebrain and may play a role in cholinergic cell dysfunction in Alzheimer's disease. We report a detailed evaluation of galanin receptors in human basal forebrain (67 +/- 12 years) and hypothalamus (67 +/- 15 years) with radioligand binding techniques. The binding of [125I]galanin (porcine) (agonist) or [125I]galantide [GAL (1-3)-substance P (5-11)-NH2] (putative antagonist) saturated in 2 hr, and only 15% to 30% of either radioligand was removed in the presence of unlabeled peptide. [125I]Galanin or [125I]galantide binding in basal forebrain revealed similar Bmax values, with [125I]galanin having a higher affinity for the galanin receptor. In contrast, [125I]galanin showed a lower affinity and labeled 42% more receptors than [125I]galantide in the hypothalamus. Differences were noted in competition studies of galanin and galanin chimeric peptides (M15, M35, M40 and C7) between [125I]galanin and [125I]galantide binding and in both regions. M35, M40 and C7 showed high affinity for galanin receptors in the hypothalamus with Hill coefficients close to unity, whereas in the basal forebrain these peptides competed differently. 5'-Guanylylimidodiphosphate reduced the specific binding of either radioligand in both regions. Based on the derived data, both radioligands irreversibly bind with high affinity and act as agonists at galanin receptors in human basal forebrain and hypothalamus. Galanin and galanin chimeric peptides compete differently for galanin receptors depending on the radioligand and region tested, suggesting subtype differences.
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PMID:Galanin receptors in human basal forebrain differ from receptors in the hypothalamus: characterization using [125I]galanin (porcine) and [125I]galantide. 747 59

Galanin, a 29 amino acid peptide, has been reported to possess antinociceptive properties at the spinal site and to potentiate opioid-induced antinociception. Our aim was to investigate whether also endogenous galanin interacts with an exogenously administered opioid, morphine, in the rat spinal cord. This question was investigated by use of the recently developed galanin receptor antagonists galantide [M-15, galanin-(1-13)-substance P-(5-11) amide] and M-35 [galanin-(1-13)-bradykinin-(2-9) amide]. Nociception was assessed in the rat tail-flick test using radiant heat and the rat Randall-Selitto model of inflammatory pain using vocalization as the nociceptive criterion. Intrathecal (i.t.) injections were performed in rats under either anaesthesia. Morphine was administered either i.t. or intraperitoneally (i.p.), and the antagonists were injected i.t. [125I]Galanin binding experiments were performed on crude synaptosomal membranes of the rat spinal cord. In the rat tail-flick test, i.t. injection of 3 micrograms morphine evoked antinociception of about 75% of the maximal possible effect (% MPE). Co-injection of either 2 micrograms galantide or 2 micrograms M-35 with morphine almost completely abolished the antinociceptive effect of morphine. I.p. injection of 2.15 mg/kg morphine elicited about 80% MPE when given 10 min prior to i.t. saline injection. Injection of the antagonists instead of saline antagonised the antinociceptive effect of morphine partially thus showing the spinal proportion of the overall antinociceptive effect. In the rat Randall-Selitto test, 3 micrograms morphine, injected i.t., produced antinociception of almost 100% MPE.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Spinal antinociception by morphine in rats is antagonised by galanin receptor antagonists. 753 Dec 94

Galanin has numerous effects on gastrointestinal smooth muscle. However, because of the lack of specific inhibitors, it is not known which are physiological and which are pharmacological. This study investigates the ability of two chimeric galanin analogs, [# 1-galantide = (M-15) = [galanin (1-13)-substance P(5-11)] and #2-M-35[galanin(1-13)bradykinin (2-9)], which were recently reported to function as galanin-receptor antagonists in the CNS, to interact with galanin receptors on rat jejunal muscle strips or dispersed smooth muscle cells from guinea pig stomach. In both systems each chimeric analog had agonist activity and was as efficacious as galanin. Cross-desensitization experiments demonstrated that in the jejunal muscle strips, both chimeric analogs were causing muscle contraction by interacting with the galanin receptor. In dispersed smooth muscle cells, galanin, as well as each chimeric analog, caused muscle relaxation, whereas substance P and bradykinin both caused muscle contraction. Each chimeric analog was equipotent to galanin in inhibiting binding of 125I-galanin, and there was close agreement between their abilities to occupy the galanin receptor and cause relaxation. Each chimeric analog also activated adenylate cyclase and increased cAMP characteristic of relaxants. These studies demonstrate these chimeric analogs will not be useful for defining the physiological role of galanin in altering gastrointestinal motility, because they function as full galanin-receptor agonists instead of as galanin-receptor antagonists.
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PMID:Chimeric galanin analogs that function as antagonists in the CNS are full agonists in gastrointestinal smooth muscle. 768 5

Galanin is a neuroendocrine peptide which is 29/30 amino acids in length and is recognised by G-protein-coupled central nervous system receptors via its N-terminus. We synthesised several galanin receptor ligands and fragments around C-terminal extensions of galanin(1-13) to yield chimeric peptides with C-terminals corresponding to bioactive peptides like bradykinin(2-9), mastoparan, neuropeptide Y(25-36) or substance P(5-11), respectively. We also synthesised short galanin analogs in which galanin(1-13) was C-terminally elongated with Lys14; different pharmacologically active small molecules were then attached to the epsilon-amino group of Lys14. Several cysteine-substituted linear and ring closed analogs of galanin(1-9) and galanin(1-16) were also synthesised. The equilibrium binding constants for these peptides at hypothalamic galanin receptors were determined and found in the subnanomolar to micromolar range. The large number of peptides and their binding affinities presented here permit structure-activity relationship analysis of peptide-type ligands to galanin receptors.
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PMID:Novel galanin receptor ligands. 949 93

The aim of this study was to develop a rapid and accurate high throughput method of screening multiple genes across a single sample set to detect changes in gene expression in the dorsal root ganglion (DRG) following partial sciatic nerve ligation in the rat. Using Taqman quantitative RT-PCR, we show that expression of a number of genes, including galanin, vasointestinal peptide and neuropeptide Y are rapidly increased 24 h post-operation in the DRGs on the ligated side only. Other genes tested, including vanilloid receptor-1, substance P, galanin receptor-2 and housekeeping genes did not alter. Analysis of the expression of ASIC4 showed a small difference in expression at 7 days post ligation. By applying a statistical method for analysis of multiple variables, partial least squares, we show that the expression change of ASIC4 was significantly altered on the ligated side even though the change was small. This method will allow us to rapidly identify changes in expression of candidate genes that may be involved in adaptive responses in the DRG due to nerve injury.
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PMID:Determination of changes in mRNA expression in a rat model of neuropathic pain by Taqman quantitative RT-PCR. 1137 55

Recent studies have revealed that the pituitary adenylate cyclase-activating polypeptide (PACAP) might act as a psychostimulant. Here we investigated the mechanisms underlying motor hyperactivity in patients with pervasive developmental disorders, such as autism, and attention-deficit hyperactivity disorder (ADHD). We studied the effects of intracisternal administration of 6-hydroxydopamine (6-OHDA) or endocrine disruptors (EDs) on spontaneous motor activity (SMA) and multiple gene expression in neonatal rats. Treatment with 6-OHDA caused significant hyperactivity during the dark phase in rats aged 4-5 weeks. Motor hyperactivities also were observed after treatment with endocrine disruptors, such as bisphenol A, nonylphenol, diethylhexyl phthalate and dibutyl phthalate, during both dark and light phases. Gene-expression profiles produced using cDNA macroarrays of 8-week-old rats with 6-OHDA lesions revealed the altered expression of several classes of gene, including the N-methyl-D-aspartate (NMDA) receptor 1, glutamate/aspartate transporter, gamma-aminobutyric-acid transporter, dopamine transporter 1, D4 receptor, and peptidergic elements such as the galanin receptor, arginine vasopressin receptor, neuropeptide Y and tachykinin 2. The changes in gene expression caused by treatment with endocrine disruptors differed from those induced by 6-OHDA. These results suggest that the mechanisms underlying the induction of motor hyperactivity and/or compensatory changes in young adult rats might differ between 6-OHDA and endocrine disruptors.
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PMID:Motor hyperactivity caused by a deficit in dopaminergic neurons and the effects of endocrine disruptors: a study inspired by the physiological roles of PACAP in the brain. 1551 16

Several chimeric peptides consisting of the N-terminal fragment of galanin (GAL) and C-terminal fragments of other bioactive peptides (e.g. substance P, bradykinin, neuropeptide Y, mastoparan) have been synthesized and reported as high-affinity galanin receptor antagonists. Recently we have synthesized a new chimeric peptide, GAL(1-13)-[Ala(10,11)]ET-1(6-21)-NH(2), consisting of the N-terminal fragment of GAL and the C-terminal fragment of endothelin-1 (ET-1) analogue. This chimera was previously shown to be a moderate-affinity ligand to hypothalamic galanin receptors with a K(D) value of 205 nM. However, its biological action has been unknown so far. In our studies we characterized the biological properties of this new chimeric analogue, investigating its action on rat isolated gastric smooth muscles and influence on insulin secretion from rat isolated islets of Langerhans. Data acquired in the course of our studies suggest that analogue GAL(1-13)-[Ala(10,11)]ET-1(6-21)-NH(2) does not seem to be a potent galanin receptor antagonist in the gastrointestinal tract.
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PMID:Synthesis and biological properties of new chimeric galanin analogue GAL(1-13)-[Ala10,11]ET-1(6-21)-NH2. 1598 8

The search for antiepileptic drugs that are capable of blocking the progression of epilepsy (epileptogenesis) is an important problem of translational epilepsy research. The neuropeptide galanin effectively suppresses acute seizures. We examined the ability of hippocampal galanin receptor type 1 (GalR1) and type 2 (GalR2) to inhibit kindling epileptogenesis and studied signaling cascades that mediate their effects. Wistar rats received 24-h-long intrahippocampal infusion of a GalR1/2 agonist galanin(1-29), GalR1 agonist M617 [galanin(1-13)-Gln14-bradykinin(2-9)-amide], or GalR2 agonist galanin(2-11). The peptides were administered alone or combined with an inhibitor of Gi protein pertussis toxin (PTX), Gi-protein activated K+ channels (GIRK) inhibitor tertiapin Q (TPQ), G(q/11) protein inhibitor [D-Arg1,D-Trp(5,7,9),Leu11]-substance P (dSP), or an inhibitor of intracellular Ca2+ release dantrolene. Sixteen hours into drug delivery, the animals were subjected to rapid kindling-60 electrical trains administered to ventral hippocampus every 5 min. M617 delayed epileptogenesis, whereas galanin(1-29) and galanin(2-11) completely prevented the occurrence of full kindled seizures. TPQ abolished anticonvulsant effect of M617 but not of galanin(2-11). PTX blocked anticonvulsant effects of M617 and inversed the action of galanin(1-29) and galanin(2-11) to proconvulsant. dSP and dantrolene did not modify seizure suppression through GalR1 and GalR2, but eliminated the proconvulsant effect of PTX + galanin(1-29) and PTX + galanin(2-11) combinations. We conclude that hippocampal GalR1 exert their disease-modifying effect through the Gi-GIRK pathway. GalR2 is antiepileptogenic through the Gi mechanism independent of GIRK. A secondary proconvulsant pathway coupled to GalR2 involves G(q/11) and intracellular Ca2+. The data are important for understanding endogenous mechanisms regulating epileptogenesis and for the development of novel antiepileptogenic drugs.
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PMID:Regulation of kindling epileptogenesis by hippocampal galanin type 1 and type 2 receptors: The effects of subtype-selective agonists and the role of G-protein-mediated signaling. 1669 66

Neuropeptides released from cutaneous nerves are attracting interest as modulators of inflammation in the skin. Recently, we showed that the neuropeptides galanin and galanin-like peptide potently inhibit inflammatory edema by reduction of microvascular blood flow. Reverse transcription-polymerase chain reaction analysis of murine skin revealed the expression of galanin receptors 2 and 3. The aim of the present study was to elucidate which galanin receptor subtype mediates the galanin-evoked inhibition of inflammatory edema formation in the skin. In this study, we report that AR-M1896, a non-GalR1 agonist, inhibited plasma extravasation induced by substance P and calcitonin gene-related peptide in a manner similar to galanin, confirming a non-GalR1-mediated effect. SNAP 37889, a nonpeptidergic selective antagonist of galanin receptor 3 (GalR3), dose-dependently abolished the antiedema effect of galanin. Thus, we were able to show that SNAP 37889 selectively antagonized galanin in the periphery and suggest that GalR3 is the receptor subtype mediating galanin's effects on the dermal microvasculature.
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PMID:Evidence that the modulatory effect of galanin on inflammatory edema formation is mediated by the galanin receptor 3 in the murine microvasculature. 1867 31

Therapeutic outcome in head and neck squamous cell carcinoma (HNSCC) is poor in most advanced cases. To improve therapeutic efficiency, novel therapeutic targets and prognostic factors must be discovered. Our studies have identified several G protein-coupled receptors (GPCRs) as promising candidates. Significant epigenetic silencing of GPCR expression occurs in HNSCC compared with normal tissue, and is significantly correlated with clinical behavior. Together with the finding that GPCR activity can suppress tumor cell growth, this indicates that GPCR expression has potential utility as a prognostic factor. In this review, we discuss the roles that galanin receptor type 1 (GALR1) and type 2 (GALR2), tachykinin receptor type 1 (TACR1), and somatostatin receptor type 1 (SST1) play in HNSCC. GALR1 inhibits proliferation of HNSCC cells though ERK1/2-mediated effects on cell cycle control proteins such as p27, p57, and cyclin D1, whereas GALR2 inhibits cell proliferation and induces apoptosis in HNSCC cells. Hypermethylation of GALR1, GALR2, TACR1, and SST1 is associated with significantly reduced disease-free survival and a higher recurrence rate. Although their overall activities varies, each of these GPCRs has value as both a prognostic factor and a therapeutic target. These data indicate that further study of GPCRs is a promising strategy that will enrich pharmacogenomics and prognostic research in HNSCC.
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PMID:G-Protein-Coupled Receptors: Next Generation Therapeutic Targets in Head and Neck Cancer? 2625 21


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