UNIPROT:P20366 - FACTA Search

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)

We have characterized and compared the substrate specificity of affinity-purified recombinant rat testes endopeptidase EC 3.4.24.15 (EP 24.15) with that reported for the isolated brain enzyme. Of the peptides tested, only bradykinin, dynorphin A1-8, and neurotensin were efficiently cleaved by the recombinant enzyme (kcat/Km = 3.0, 2.8 and 0.5 x 10(5) M-1sec-1, respectively); other peptides considered substrates of EP 24.15 (gonadotropin-releasing hormone, substance P, somatostatin and angiotensin) were not metabolized. The enzyme was inhibited by metal ion chelators and thiol-reactive agents, as well as a specific EP 24.15 inhibitor (N-[1(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Tyr-p-aminobenzoate), thus confirming the enzyme as a thiol-dependent metalloendopeptidase. The observed discrepancies in substrate specificity of the recombinant testicular and the isolated brain enzymes may result from tissue-specific forms and/or post-translational modifications of EP 24.15.
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PMID:Substrate specificity differences between recombinant rat testes endopeptidase EC 3.4.24.15 and the native brain enzyme. 773 70

Interleukin-1 beta (IL-1 beta) is a pleiotropic cytokine that appears to be an integral component of the bidirectional signalling between the immune and central nervous systems. It is produced in the hypothalamus and has been shown to inhibit the hypothalamo-pituitary-gonadal axis and to activate the hypothalamo-pituitary-adrenal axis. IL-1 beta is reported to up-regulate the tachykinin, substance P (SP), in the peripheral nervous system. We have recently observed that members of the hypothalamic tachykinin family including SP, neurokinin A (NKA) and two N-terminal extended forms of NKA (neuropeptides kappa and gamma), inhibit hypothalamic LHRH and pituitary LH release and stimulate adrenal corticosterone secretion. The similarity in the endocrine effects of the tachykinins and the cytokine prompted us to test the hypothesis that IL-1 beta may stimulate the hypothalamic tachykinins, which would then mediate the neuroendocrine effects of IL-1 beta. First, the effects of IL-1 beta on the in vitro release of NKA-like immunoreactivity (NKA-li) from the hypothalamus was examined. Addition of 10 nM IL-1 beta significantly increased NKA-li release from the hypothalami of castrated rats, but not from the hypothalami of intact rats. To identify the site of IL-1 beta action, the effects of intraventricular IL-1 beta (100 ng) on NKA-li levels in various hypothalamic sites of intact and castrated rats were examined. The results showed that IL-1 beta increased NKA-li selectively in the median eminence (ME) and arcuate nucleus (ARC) of castrated rats only.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effects of interleukin 1 beta on the hypothalamic tachykinin, neurokinin A. 785 71

The effects of neuropeptide Y (NPY) on LHRH release from an immortalized cell line were investigated using a flow-through cell culture superfusion system. Immortalized hypothalamic GT1-7 cells were cultured for 72 h and superfused for a total of 180 min. In initial experiments, discrete 5-min pulses of NPY (10(-12)-10(-5) M) were administered to the cells. A clear dose-dependent stimulatory effect on NPY on LHRH release from the cells was observed with a calculated 50% effectiveness concentration of 33 nM. The stimulatory effects of brief NPY exposure were rapid and robust, e.g. reaching and maintaining levels of 173% over baseline for 20 min at the 10(-7) dose. The lowest dose of NPY that showed a significant effect was 10(-10) M; maximal responses were observed at 10(-6) M and reached a plateau thereafter. Control pulses of Dulbecco's modified Eagle's medium (DMEM) and 10(-6) M substance P or arg-vasopressin were also presented to the cells to serve as controls for our pulse protocol, and these challenges produced no significant LHRH responses. The NPY receptor antagonists, PYX1 and PYX2, at 10(-8) M, completely blocked the observed NPY responses in these cells. To assess the NPY receptor subtypes that mediate the NPY effects pharmacologically, GT1-7 cells were challenged with a Y1 receptor agonist, (Leu31Pro34)NPY, a Y2 receptor agonist, NPY(13-36), or peptide YY, at doses 10(-12)-10(-5) M. All four peptides stimulated LHRH release from GT1-7 cells with a rank-ordered potency of NPY = peptide YY > Y1 agonist = Y2 agonist. To examine possible signal transduction mechanism(s) involved in mediating this effect, pertussis toxin, RpcAMPs (cyclic adenosine-3'5'-monophosphothioate Rp diastereomer), Ca(2+)-free DMEM and TMB-8 (3, 4, 5-trimethoxybenzoic acid 8-(diethylamino) octylester) were used to treat the cells before and during superfusion with NPY. Treatment with pertussis toxin, RpcAMPs, and Ca(2+)-free DMEM did not significantly alter NPY-stimulated LHRH release responses to 10(-7) M NPY. However, the addition of 100 microM and 250 microM TMB-8 to Ca(2+)-free DMEM almost completely blocked this NPY effect, as did 10 microM ryanodine. Finally, the locus of action for this NPY effect was examined using tetrodotoxin to reduce action potential propagation in the GT1-7 cells. Tetrodotoxin treatment blocked the LHRH response to NPY by more than 50%.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Neuropeptide Y stimulates luteinizing hormone-releasing hormone release from superfused hypothalamic GT1-7 cells. 792 25

In this article I have examined various aspects of the complex spatio-temporal patterning of peptidergic signaling that lead to synchronized development of neural events for the preovulatory LHRH discharge on proestrus. Undoubtedly, the integration of these events is orchestrated by both ovarian steroids, E2 and P. Evidence accumulated in recent years has failed to affirm the perceived notion that E2 is an adequate peripheral signal for the timely, robust discharge of LHRH on proestrus. The current understanding is shaped by the thesis that the concerted central actions of E2 and P are mediated by a host of regulatory peptides produced locally in the hypothalamus, and steroids, in general, augment the production and release of both inhibitory and excitatory peptides in a timely fashion to facilitate the preovulatory LHRH discharge. Since these peptidergic pathways appear mandatory for signal transfer, considerable recent research has been devoted first to identifying the signals that selectively participate in the induction of preovulatory LHRH (LH) surge, and then to trace the route of signal transmission that ultimately leads to LHRH hypersecretion on the afternoon of proestrus (Fig. 1). The peptidergic pathways that propagate and transmit impulses for the preovulatory LHRH discharge reside in the SCN-MPN-MPOA-ARC-ME neural complex (Fig. 1). The timely initiation of these impulses is entrained to the photo-periodic input reaching the SCN by the retino-hypothalamic tract. The evidence is already in place to show that further information processing is transduced in the MPN; however, the nature of neurochemical signaling between the two sites remains to be deciphered. The available evidence favors a mandatory participation of inhibitory (EOP and NPK) and excitatory (NPY, GAL, NT, and AII) messenger molecules within the SCN-MPN-MPOA-ARC-ME complex (Fig. 1). It is possible that the relevant information from the SCN-MPN is conveyed caudally to the ARC in order to initiate a chain of events for disinhibition/excitation of the NPY-EOP network and to affect LHRH neurosecretion at the perikaryal level in the MPOA and at axon terminals in the ME. Also, either concurrently or on a time-delayed basis, the relevant information from the MPN may be relayed to the MPOA via the local peptidergic network comprised of NT, EOP, NPK, and GAL. This transmission may initially be critical for elicitation of antecedent neurosecretory events in the ME and to ultimately evoke the preovulatory LHRH surge.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mandatory neuropeptide-steroid signaling for the preovulatory luteinizing hormone-releasing hormone discharge. 826 4

A large body of recent evidence suggests that a number of inhibitory and excitatory neuropeptides and amino acids may participate in the episodic secretion of hypothalamic LHRH and pituitary LH in castrated rats. However, the precise functional relationships among these messenger molecules in the control of LH secretion remain to be ascertained. The aim of this study was to test the hypothesis that inhibition of LH release by an opioid [beta-endorphin (beta END)], cytokine [interleukin-1 beta (IL-1 beta)], or tachykinin [neuropeptide-K (NPK)] is a result of diminished excitatory amino acid (EAA) signaling. Adult male rats were castrated and received an intracerebroventricular cannula in the third ventricle for administration of beta END (10 micrograms/rat), NPK (2.5 nmol/rat), or IL-1 beta (100 ng/rat) 2 weeks postcastration. One day before the experiments, rats received an intraatrial cannula for frequent blood sampling and for iv injection of the glutamate receptor agonist N-methyl-D-aspartate (NMDA; 5 mg/kg) at 30-min intervals. Blood samples for LH measurements were withdrawn immediately before and 10 min after each NMDA injection. The results show that intracerebroventricular beta END, IL-1 beta, or NPK inhibited LH release. Multiple injections of NMDA did not alter the existing pattern of LH secretion in castrated control rats. However, similar NMDA injections completely prevented the decrease in LH release by beta END, IL-1 beta, or NPK. Plasma LH levels in these rats remained within the range seen in untreated control rats throughout the 120-min duration of the experiment, and NMDA injections at 30-min intervals evoked pulses of LH that resembled those seen normally in castrated rats. The blockade of the inhibitory effects of the three peptides by NMDA and previous knowledge of hypothalamic sites of NMDA action suggest that EAA systems may represent a common pathway down-stream in the hypothalamic LHRH-regulating circuitry to mediate diminution of LH release by inhibitory peptides. Further, their inhibitory influence may be exerted either directly at the level of LHRH neurons and/or by diminution in EAA efflux, leading to suppression of LHRH and LH release.
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PMID:Evidence that luteinizing hormone suppression in response to inhibitory neuropeptides, beta-endorphin, interleukin-1 beta, and neuropeptide-K, may involve excitatory amino acids. 831 64

The action of neuropeptides at the synapse is terminated through enzymatic degradation by membrane-bound proteases. We defined and purified membrane-bound proteases functioning at the initial stage of degradation of four neuropeptides. 1. Substance P-degrading endopeptidases isolated from the rat brain and pig striatum showed similar properties to those of endopeptidase-24.16 (neurolysin) except for cleavage sites of substance P. 2. LHRH fragment (1-5)-generating endopeptidases isolated from the neuroblastoma cells and rat brain showed similar properties to those of endopeptidase-24.15 (thimet oligopeptidase). 3. One of two dynorphin-degrading cysteine proteases isolated from neuroblastoma cells showed strict specificity toward the Arg-Arg residues. 4. Endopeptidase-24.11 (neprilysin) isolated from the rat brain was identified as a somatostatin-degrading enzyme.
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PMID:[Membrane-bound proteases involved in neuropeptide degradation in the brain]. 836 28

Bovine median eminence contains a factor difference from gonadotropin-releasing hormone (GnRH) than increases basal luteinizing hormone (LH) secretion and potentiates GnRH-stimulated LH release. We compared the effect of hypothalamic neuropeptides on basal and GnRH-stimulated LH secretion using rat pituitary cells under static incubation conditions to determine if any of them mimics the LH-releasing activity no attributable to GnRH present in bovine median eminence extracts. Both, galanin and neurotensin (10(-9)-10(-5)) stimulated basal LH secretion in a dose-response manner. Galanin increased 3-4 fold and neurotensin doubled the basal LH secretion. The GnRH antagonist Nal-Glu 10(-6) M abolished the effect of 10(-7) M GnRH and 10(-5)M neurotensin, but did not block the LH-releasing activity of galanin. Leucin-enkephalin, beta-endorphin, substance P and neuropeptide Y (NPY) did not alter basal LH secretion. Neuropeptides produced three types of response on GnRH-stimulated LH release. First, leucine-enkephalin and beta-endorphin (10(-9)-10(-5) M) showed a dose-dependent inhibition of GnRH-stimulated LH release. At 10(-5) M the inhibition was complete with leucine-enkephalin and only 30% with beta-endorphin. Both were blocked by naloxone. Second, substance P showed an inverted U type response on GnRH-stimulated LH secretion. At 10(-9) M this peptide potentiated the action of GnRH. This effect decreased when the dose of substance P was increased to 10(-7) M and turned inhibitory at 10(-5) M when 10(-7) M GnRH was used. Third, galanin and NPY potentiated the effect of GnRH on LH secretion. Neurotensin had no effect on GnRH-stimulated LH release. In conclusion, rat gonadotrophs present diverse responses to neuropeptides at physiological concentrations, and -apart from GnRH-galanin is most likely the other factor present in bovine median eminence extracts that stimulates LH secretion. The data lend further support to a role of galanin in the control of LH secretion.
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PMID:Comparison of the effect of hypothalamic neuropeptides upon luteinizing hormone secretion by cultured rat anterior pituitary cells. 864 Feb 40

Endothelins (ETs) were initially thought to be primarily involved in the control of cardiovascular activity, but the presence of ETs and their receptors in a wide variety of other tissues has suggested a much broader range of functions. Specific receptors for ETs are found in nonvascular tissues including neuronal, neuroendocrine, and endocrine cells. In addition, immunoreactive ETs are present in the brain, pituitary, and peripheral endocrine tissues. However, the ET levels in hypothalamo-hypophysial portal and peripheral blood are low, suggesting that the ET system participates in neuroendocrine regulation through paracrine and/or autocrine mechanisms. Both ETA and ETB receptors are expressed in the hypothalamus, adrenal, parathyroid glands, pancreas, ovary, uterus, placenta, and prostate, while only ETA receptors are expressed in GT1 neurons, anterior pituitary cells, alpha T3-1 immortalized gonadotropes, parathyroid-derived cells, thyrocytes, testicular Leydig and Sertoli cells, normal and neoplastic ovarian granulosa cells, chondrocytes, and other cell types. Activation of ET receptors elicits the sequence of cellular events typical of Ca(2+)-mobilizing receptors, with prominent increases in phosphoinositide hydrolysis and elevations of [Ca2+]i that occur in oscillatory and nonoscillatory modes depending on the cell type. ET-induced activation of the phosphoinositide/Ca(2+)- mobilizing pathway in neuronal and endocrine cells is associated with rapid stimulation of secretory responses, including release of gonadotropin-releasing hormone, oxytocin, vasopressin, substance P, atrial natriuretic peptides, gonadotropins, thyrotropin, growth hormone, parathyroid hormone, aldosterone, and catecholamines. On the other hand, ET has inhibitory actions on prolactin, progesterone, and renin release. In addition to stimulating phospholipase C-dependent pathways, ETs also activate phospholipase D-and MAP-kinase-dependent pathways in some of their target cells, as well as expression of early response genes and increased mitogenic activity. In many neuroendocrine cells, ET induces rapid and marked desensitization of its signaling system, in association with extensive internalization of ET receptors and reduced signaling and secretory responses. These findings raise the possibility that ETs participate in the control of secretory responses in the hypothalamo-pituitary system and peripheral endocrine cells, as well as in long-term aspects of regulation in certain neuroendocrine cells.
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PMID:Expression and signal transduction pathways of endothelin receptors in neuroendocrine cells. 881 99

Prolyl endopeptidase has been predominantly described as a cytosolic activity capable of cleaving a number of important neuropeptides (including TRH, LHRH, Bradykinin, Angiotensin, Substance P, Neurotensin, Oxytocin and Vasopressin) on the carboxy side of proline. In this paper, we report, for the first time, on the complete purification and characterization of a membrane-bound form of prolyl endopeptidase. This novel activity has been isolated from the synaptosomal (plasma membranes) membranes of bovine brain. Following gel filtration, hydroxylapatite and hydrophobic interaction chromatographies, the prolyl endopeptidase activity was purified 1400-fold with a 23% recovery of activity. The enzyme was shown to have a relative molecular mass of 87 kDa and a Km of 60 microM for its specific fluorimetric substrate, Z-GlyProMCA. The purified enzyme demonstrated a relatively broad substrate specificity and a relatively high affinity for proline-containing neuropeptides. It was shown to be inhibited by certain thiol-protease inhibitors and by the metal chelator, 1,10-phenanthroline, thus possibly classifying it as a 'thimet' activity. The purified particular form of proyl endopeptidase displayed a similar substrate specificity to the previously reported cytosolic forms of the enzyme. However, there were differences between the two forms in term of their sensitivity to inhibitors, their affinities for the peptide substrates and their relative molecular masses. The different subcellular location (i.e. the synaptosomal membrane) of the particulate prolyl endopeptidase is also of potential physiological significance given that here it is more likely to come in contact with the vesicle-bound neuropeptides than is its cytosolic counterpart.
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PMID:Purification and characterization of a novel membrane-bound form of prolyl endopeptidase from bovine brain. 902 55

The various cell groups in the human hypothalamus show different patterns of aging, which are the basis for changes in biological rhythms, hormone production, autonomic functions, and behavior. The suprachiasmatic nucleus (SCN), the clock of the brain, exhibits circadian and seasonal rhythms in vasopressin synthesis that are disrupted later in life. Furthermore, the age-related sexual differences in the number of vasoactive intestinal polypeptide neurons in this nucleus reinforces the idea that the SCN is not only involved in the timing of circadian rhythms but also in the temporal organization of reproductive functions. The sexually dimorphic nucleus of the preoptic are (SDN-POA), or intermediate nucleus, is twice as large in men as in women, a difference that arises between the ages of two to four years and puberty. During aging a dramatic, sex-dependent decrease in cell number occurs, leading to values which are only 10-15% of the cell number found in early childhood. The vasopressin and oxytocin producing cells in the supraoptic nucleus (SON) and paraventricular nucleus (PVN) are examples of neuron populations that seem to stay perfectly intact in old age. Parvocellular corticotropin-releasing hormone-containing neurons are found throughout the PVN and are even activated in the course of aging, as indicated by their increase in number and by their coexpression with vasopressin. Part of the arcuate nucleus of the hypothalamus (ARH), or tubero-infundibular nucleus, contains hypertrophic neurons in postmenopausal women. These hypertrophied neurons contain neurokinin-B, substance P, and estrogen receptors and probably act on LHRH neurons as interneurons. The tuberal lateral nucleus (NTL), involved in feeding behavior and energy metabolism, does not show any neuronal loss in senescence. These findings indicate that each cell group of the human hypothalamus has its own sex-specific pattern of aging. In fact, some hypothalamic nuclei show a dramatic functional decline with aging, whereas others seem to become more active later in life.
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PMID:Lifespan changes in the human hypothalamus. 931 57

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