UNIPROT:P20366 - FACTA Search

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Query: UNIPROT:P20366 (substance P)
21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neurons of the medullary raphe project widely to respiratory and autonomic nuclei and contain co-localized serotonin, thyrotropin-releasing hormone (TRH), and substance P, three neurotransmitters known to stimulate ventilation. Some medullary raphe neurons are highly sensitive to pH and CO(2) and have been proposed to be central chemoreceptors. Here it was determined whether these chemosensitive neurons are serotonergic. Cells were microdissected from the rat medullary raphe and maintained in primary cell culture for 13-70 days. Immunoreactivity for serotonin, substance P, and TRH was present in these cultures. All acidosis-stimulated neurons (n = 22) were immunoreactive for tryptophan hydroxylase (TpOH-IR), the rate-limiting enzyme for serotonin biosynthesis, whereas all acidosis-inhibited neurons (n = 16) were TpOH-immunonegative. The majority of TpOH-IR medullary raphe neurons (73%) were stimulated by acidosis. The electrophysiological properties of TpOH-IR neurons in culture were similar to those previously reported for serotonergic neurons in vivo and in brain slices. These properties included wide action potentials (4.55 +/- 0.5 ms) with a low variability of the interspike interval, a postspike afterhyperpolarization (AHP) that reversed 25 mV more positive than the Nernst potential for K(+), prominent A current, spike frequency adaptation and a prolonged AHP after a depolarizing pulse. Thus the intrinsic cellular properties of serotonergic neurons were preserved in cell culture, indicating that the results obtained using this in vitro approach are relevant to serotonergic neurons in vivo. These results demonstrate that acidosis-stimulated neurons of the medullary raphe contain serotonin. We propose that serotonergic neurons initiate a homeostatic response to changes in blood CO(2) that includes increased ventilation and modulation of autonomic function.
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PMID:Acidosis-stimulated neurons of the medullary raphe are serotonergic. 1135 37

We immunohistochemically examined neurotransmitter systems, which function in the brainstem and are involved in neuronal organization of respiration, in an autopsy brain from a patient with Rett syndrome (RS). Immunoreactivity (IR) for tyrosine hydroxylase, a functional marker for catecholaminergic neurons, was severely reduced in the locus ceruleus, while that for tryptophan hydroxylase involved in serotonin synthesis was spared in the raphe nuclei. In the brainstem, IR for substance P (SP) was reduced in the parabrachial complex and that for methionine-enkephalin (met-enk) was affected in the parabrachial, hypoglossal, dorsal vagal and solitary nuclei. In addition, expressions of these neuropeptides were also disturbed in the basal ganglia. A widespread altered expression of antagonistic neuropeptides, SP and met-enk, may be involved in the pathogenesis of RS, especially in its respiratory manifestation.
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PMID:Reduced expression of neuropeptides can be related to respiratory disturbances in Rett syndrome. 1173 57

Substance P (SP) is known to act at supraspinal sites to influence pain sensitivity as well as to promote anxiety. The effects of SP could be mediated in part by actions in the periaqueductal gray (PAG) and the dorsal raphe nucleus (DRN), adjoining mesencephalic cell groups that are strategically positioned to influence both nociception and mood. Previous studies have indicated that SP regulates both enkephalin and serotonin neurotransmission in these brain regions. To determine the mechanism underlying the effects of SP in the PAG and DRN, the distribution of the principal receptor for SP, the neurokinin 1 (NK1) receptor, was examined with respect to other neurotransmitter markers. PAG neurons that had NK1 receptor immunolabeling were interdigitated with and received contacts from enkephalin-containing neurons. However, only a few (16/144; 11%) neurons with NK1 receptor also contained enkephalin immunoreactivity after colchicine treatment. In the DRN, dendrites containing NK1 receptor were selectively distributed in the dorsomedial subdivision. The majority (132/137; 96%) of these dendrites did not contain immunoreactivity for the serotonin-synthesizing enzyme tryptophan hydroxylase. In contrast, neuronal profiles with NK1 receptor in both the PAG and the DRN often contained immunolabeling for glutamate. Light and electron microscopic examination revealed that 48-65% of cell bodies and dendrites with NK1 receptor were dually immunolabeled for glutamate. These data suggest that SP directly acts primarily on glutamatergic neurons in the PAG and DRN. To a lesser extent, enkephalin-containing neurons may be targeted. Through these actions, it may subsequently influence activity of larger populations of neurons containing enkephalin as well as serotonin. This circuitry could contribute to, as well as coordinate, effects of SP on pain perception and mood.
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PMID:Cellular basis for the effects of substance P in the periaqueductal gray and dorsal raphe nucleus. 1196 97

Developmental studies on neurotransmitters and their receptors in sudden infant death syndrome (SIDS) infants and controls are reviewed, including comparison between the prone and supine positions at death. In SIDS infants, there are an increase of glial fibrillary acidic protein (GFAP)-positive astrocytes in the brainstem, an increase of substance P (SP) in the medulla and pons, a decrease of tyrosine hydroxylase (TH)-positive catecholaminergic neurons in the ventrolateral medulla (VLM), and vagal nuclei in the medulla oblongata and basal ganglia, a decrease of tryptophan hydroxylase (TrH)-positive serotonergic neurons in the periaqueductal gray matter (PAG), and decreases of 5-hydroxytryptamine 1A (5-HT1A) and 5-HT2A receptor immunoreactivities in the VLM and vagal nuclei in the medulla oblongata. These findings may be the result of chronic or repeated hypoxia and at the same time suggest hypofunction or immaturity of cardiorespiratory regulation. In contrast, 5-HT1A and 5-HT2A receptor immunoreactivities are increased in the PAG of SIDS infants. These increased immunoreactivities may reflect delayed neuronal maturation or a developmental abnormality of the nocicetive reaction of cardiorespiratory and arousal control in SIDS. Also, there are no differences of brainstem gliosis and catecholaminergic neuron changes between the prone and supine positions. Therefore, these changes may be predisposing factors for SIDS.
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PMID:Developmental neurotransmitter pathology in the brainstem of sudden infant death syndrome: a review and sleep position. 1235 Mar 1

Pharmacogenetic studies in mood disorders are raising increasing interest, after the first findings of a significant association between antidepressant response and a functional polymorphism in the upstream regulatory region of the serotonin transporter gene (SERTPR). However, the results of published studies are not unequivocal. The reasons of these discordances could be various: the small samples, which could affect the power to detect a good effect size, the use of different and often not comparable scales and methodologies to assess the response rates. Notwithstanding all these limitations, the choice of candidate genes involved in antidepressant response is one of the crucial steps to target future research. In the present paper, we reviewed the literature concerning pharmacogenetic studies on antidepressant response. This analysis evidenced a number of studies consistently confirming the association of the SERTPR short variant with a poorer response to antidepressants, at least for the Caucasian samples. Further unreplicated positive findings included tryptophan hydroxylase (TPH), G-protein beta(3)-subunit (Gbeta(3)) and serotonin receptor 2A gene polymorphisms. Through the review, we also suggested possible candidate genes for future studies, which are involved in the main monoaminergic neurotransmitters pathways (norepinephrine, dopamine, serotonin), in substance P, neurokinines and glutamate systems, in the intracellular signal transduction pathway, in the phosphorylation process and in the control of the transcriptional activity system.
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PMID:From molecular biology to pharmacogenetics: a review of the literature on antidepressant treatment and suggestions of possible candidate genes. 1499 79

The major objective of this study was to gain insight into whether under physiological conditions medullary raphe area neurons influence breathing through CO(2)/H(+) chemoreceptors and/or through a postulated, nonchemoreceptor modulatory influence. Microtubules were chronically implanted into the raphe of adult goats (n = 13), and breathing at rest (awake and asleep), breathing during exercise, as well as CO(2) sensitivity were assessed repeatedly before and after sequential injections of the neurotoxins saporin conjugated to substance P [SP-SAP; neurokinin-1 receptor (NK1R) specific] and ibotenic acid (IA; nonspecific glutamate receptor excitotoxin). In all goats, microtubule implantation alone resulted in altered breathing periods, manifested as central or obstructive apneas, and fractionated breathing. The frequency and characteristics of the altered breathing periods were not subsequently affected by injections of the neurotoxins (P > 0.05). Three to seven days after SP-SAP or subsequent IA injection, CO(2) sensitivity was reduced (P < 0.05) by 23.8 and 26.8%, respectively, but CO(2) sensitivity returned to preinjection control values >7 days postinjection. However, there was no hypoventilation at rest (awake, non-rapid eye movement sleep, or rapid eye movement sleep) or during exercise after these injections (P > 0.05). The neurotoxin injections resulted in neuronal death greater than three times that with microtubule implantation alone and reduced (P < 0.05) both tryptophan hydroxylase-expressing (36%) and NK1R-expressing (35%) neurons at the site of injection. We conclude that both NK1R- and glutamate receptor-expressing neurons in the medullary raphe nuclei influence CO(2) sensitivity apparently through CO(2)/H-expressing chemoreception, but the altered breathing periods appear unrelated to CO(2) chemoreception and thus are likely due to non-chemoreceptor-related neuromodulation of ventilatory control mechanisms.
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PMID:Transient attenuation of CO2 sensitivity after neurotoxic lesions in the medullary raphe area of awake goats. 1532 66

Xeroderma pigmentosum group A (XPA) is a hereditary disorder characterized by cutaneous symptoms and progressive neurodegeneration. Since XPA patients exhibit peripheral neuropathy, neuronal deafness, rigidity, dysphagia, and laryngeal dystonia, it is indispensable for investigation of the neurodegeneration to analyze brainstem and basal ganglia lesions clinically and pathologically; we have previously shown the role of oxidative stress in the development of basal ganglia lesions. Here we immunohistochemically examined the expression of neurotransmitters, calcium-binding proteins, and neuropeptides in the brainstem, basal ganglia, and thalamus in 5 XPA autopsy cases. In the brainstem, immunoreactivity for tyrosine hydroxylase, tryptophan hydroxylase, and calbindin-D28K was severely reduced throughout the brainstem in all the XPA cases. Nevertheless, the expressions of parvalbumin, substance P, and methionine-enkephalin in the brainstem were comparatively preserved; the exception being reduced immunoreactivity for them in the cochlear and dorsal column nuclei in 3 cases. The large cell neurons in the putamen were preferentially reduced, the immunoreactivity for tyrosine hydroxylase reflecting the dopaminergic afferent and efferent pathways was severely affected, and the expression of 3 calcium binding proteins (i.e. parvalbumin, calbindin-D28K, and calretinin) was disturbed in various ways. The expression of substance P and methionine-enkephalin, which are involved in the efferent pathways in the basal ganglia, in the globus pallidus and substantia nigra was spared. It is speculated that the selective damage to the dopamine system in the basal ganglia and the disturbed monoaminergic expression in the brainstem could be related to clinical abnormalities such as the rigidity, laryngeal dystonia, and several neurophysiological changes. Functional analysis of autopsy brains will facilitate clarification of the pathogenesis of the neurodegeneration in XPA.
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PMID:Brainstem and basal ganglia lesions in xeroderma pigmentosum group A. 1553 32

In addition to its neurotransmitter/modulator role in pain perception, substance P (SP) is involved in a regulation of mood, as antagonists of its neurokinin-1 receptor (NK1r) have been found to have antidepressant-like effects in humans. In rodents, treatment with NK1r antagonists has been shown to increase the firing of dorsal raphe nucleus (DRN) serotonin (5-hydroxytryptamine, 5-HT) neurons and to induce a desensitization of their 5-HT1A autoreceptors, suggesting local interactions between the SP and 5-HT systems. To search for the presence of NK1r on 5-HT neurons of the DRN, we used light and electron microscopic immunocytochemistry, as well as confocal microscopy, after single- and double-labelling of NK1r and of the biosynthetic enzyme of 5-HT, tryptophan hydroxylase (TpOH). A significant number of 5-HT (TpOH-positive) cell bodies and dendrites endowed with NK1r were thus demonstrated in the caudal part of rat and mouse DRN. As visualized by electron microscopy after gold immunolabelling, NK1r was mostly cytoplasmic in 5-HT neurons, while predominating on the plasma membrane in the case of TpOH-negative dendrites. The proportion of NK1r observed on the plasma membrane of 5-HT neurons was, however, slightly higher in mouse than rat. Thus, in both rat and mouse DRN, a subpopulation of 5-HT neurons is endowed with NK1r receptors and may be directly involved in the antidepressant-like effects of NK1r antagonists. These 5-HT neurons represent a new element in the neuronal circuitry currently proposed to account for the role of SP in mood regulation.
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PMID:Immunocytochemical evidence for the existence of substance P receptor (NK1) in serotonin neurons of rat and mouse dorsal raphe nucleus. 1681 84

Small intestinal carcinoids (SICs) are the most prevalent gastrointestinal carcinoid and characterized by local invasion metastasis and protean symptomatology. The proliferative and secretory regulation of the cell of origin, the enterochromaffin (EC) cell has not been characterized. The absence of either a pure preparation of normal EC cells or human EC carcinoid cell lines has hindered the development of therapeutic agents. We therefore further characterized the neoplastic SIC cell line, KRJ-I by assessing its secretory (serotonin (5-HT)) and proliferative responses and defining its log growth phase transcriptome. Electron microscopy demonstrated oval, lobulated nuclei and substance P, and 5-HT-positive cytoplasmic vesicles. RT-PCR detected transcripts for chromogranin A (CHGA), VMAT1 (SLC18A1), tryptophan hydroxylase (TPH1), substance P (TAC1), guanylin (GUCA2A), and SERT (SLC6A4). By immunohistochemistry, all cells were positive for CHGA, SERT, VMAT1, and TPH1. Transcriptome analysis (Affymetrix U133 Plus chips) identified somatostatin SSTR2/3, adrenergic alpha1C and beta1, dopamine D2, nicotinic-type cholinergic A5, A6, B1, muscarinic acetylcholine M4, and 5-HT-2A receptors. The presence of transcripts for SSTR1, SSTR2, and SSTR3 receptors was confirmed by RT-PCR and sequencing. Isoproterenol (ISO) resulted in a dose-dependent increase in intracellular cAMP (EC50=340 nM) and 5-HT (EC50=81 nM) which was completely inhibited by the cAMP antagonist 2',5'-dideoxyadenosine (10 microM). Preincubation with a SSTR agonist, lanreotide, inhibited Ip-stimulated 5-HT secretion (IC50=420 nM). Both lanreotide (10 nM) and rapamycin (50 nM) inhibited proliferation (20+/-12 and 35+/-5% respectively) in serum-free medium whereas gefitinib (1 nM-10 microM) inhibited proliferation at micromolar concentrations. KRJ-I is a neoplastic EC cell line that can be used as an in vitro model of SICs as it will allow elucidation and clarification of the secretory and proliferative mechanism(s) of neoplastic EC cells and the molecular signatures that characterize each of these responses.
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PMID:Further delineation of the continuous human neoplastic enterochromaffin cell line, KRJ-I, and the inhibitory effects of lanreotide and rapamycin. 1724 79

In order to investigate epileptogenesis in hereditary dentatorubral-pallidoluysian atrophy (DRPLA), we immunohistochemically examined the expression of neurotransmitters, neuropeptides, calcium-binding proteins and/or glutamate transporters in the brainstem and cerebral cortex in autopsy cases. The subjects comprised 14 cases of clinicopathologically confirmed DRPLA, including 7 cases of juvenile and 2 cases of early adult types with progressive myoclonus epilepsy (PME), 5 cases of late adult type without PME, and 10 age-matched controls. Serial sections of the brainstem and cerebral cortex were treated with antibodies to tyrosine hydroxylase, tryptophan hydroxylase, substance P, methionine-enkephalin, parvalbumin, calbindin-D28K, calretinin, and excitatory amino acid transporters. Although the size of the tegmentum was small, we failed to find any PME-specific brainstem changes in the expression of neurotransmitters, neuropeptides and calcium-binding proteins. The number of interneurons immunoreactive for calbindin-D28K and parvalbumin, markers of GABAergic inhibitory interneurons, were reduced throughout the cerebral cortex, but there was no significant difference in the density of immunoreactive neurons between DRPLA patients of each type. The expression of glutamate transporters was comparatively spared. The current study revealed an absence of PME-specific brainstem lesions and indicated a possible involvement of the reduced GABAergic interneurons in the cerebral cortex in formation of PME in DRPLA.
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PMID:Neuropathological analysis of the brainstem and cerebral cortex lesions on epileptogenesis in hereditary dentatorubral-pallidoluysian atrophy. 1730 19

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