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

The biosynthetic enzyme peptidylglycine alpha-amidating monooxygenase catalyzes the formation of a variety of biologically active alpha-amidated peptides from respective COOH-terminal glycine-extended peptide precursors. Peptidylglycine alpha-amidating monooxygenase activity is dependent on copper, ascorbate, and molecular oxygen and is inhibited by the relatively selective copper chelator N,N-diethyldithiocarbamate or its disulfide dimer disulfiram (Antabuse). In the present study, chronic disulfiram treatment (100 mg/kg/day, for 12-25 days) resulted in significant changes in several neurochemical parameters in the mouse central nervous system, including levels of substance P-like, unamidated substance P-Gly-like, and protease-generated substance P-Gly-Lys-like immunoreactivities (SP-LI, SP-G-LI, and SP-G-K-LI, respectively). Combined high performance liquid chromatography/radioimmunoassay analyses of the extracted SP-LI, SP-G-LI, and SP-G-K-LI species indicated very similar chromatographic and immunochemical behavior as demonstrated for chemically authentic peptide standards. Additionally, changes in levels of monoamines and their metabolites were observed after drug administration. Complementary immunohistochemical analyses using affinity-purified anti-SP-G sera localized these drug-induced changes in levels of immunoreactive unamidated precursor to neural elements that normally express SP. As a functional corollary to alterations in neurochemical parameters, we observed significant disulfiram-induced increases in pain thresholds, potentiated by capsaicin treatment. Overall, our results indicate that the observed changes in steady state levels of immunoreactive SP and of the immature COOH-terminal extended forms of SP may reflect compensatory biosynthetic and posttranslational processing events in SP-containing neural systems after pharmacological challenge.
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PMID:Disulfiram administration affects substance P-like immunoreactive and monoaminergic neural systems in rodent brain. 168 29

The effects of the neuropeptides VIP, PHM and substance P (SP) on vascular smooth muscle tone, K+ secretion from exocrine elements and tissue content of cyclic AMP (cAMP) in the human submandibular gland were studied in vitro. All three peptides caused relaxation of noradrenaline contracted human submandibular arteries at nM concentrations. SP was slightly more active than VIP and PHM which had a similar potency as vasodilators. Only carbachol but not VIP, PHM or SP stimulated K+ secretion from exocrine elements of the human submandibular gland. Principally similar in vitro effects on K+ secretion were obtained on the cat submandibular gland, but in the rat not only carbachol but also SP stimulated K+ secretion. VIP and PHM increased cAMP production of exocrine elements in the human submandibular gland in nM concentrations. VIP was about 5-fold more potent than PHM with regards to cAMP production. In conclusion, VIP, PHM and SP relaxed human submandibular arteries in vitro. Both VIP and PHM stimulated cAMP production in glandular tissue but none of the three peptides induced K+ secretion from human submandibular gland tissue. This suggests that, in contrast to the situation in the rat, SP does not cause watery salivation in man, while VIP and PHM may modulate protein e.g. amylase content of the saliva.
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PMID:Effects of VIP, PHM and substance P on blood vessels and secretory elements of the human submandibular gland. 242 7

In addition to classical cholinergic and adrenergic neural mechanisms, a third division of autonomic control has been recognised in human airways. Non-adrenergic inhibitory nerves are the dominant inhibitory neural pathway in human airway smooth muscle and there is increasing evidence that VIP and a related peptide, PHM, may be the neurotransmitters. These peptides are probably cotransmitters of acetylcholine in the airways and may modulate cholinergic effects. A defect in this system could occur in asthma because inflammation may more rapidly inactivate these neurotransmitter peptides. Non-cholinergic excitatory nerves have also been described in animal airways, although their existence in human airways is less certain. The neurotransmitter may be substance P or a related peptide neurokinin A, which could be released by axon reflex. Another peptide, calcitonin gene-related peptide, is colocalized with substance P and appears to be much more potent in human airways. Non-adrenergic non-cholinergic mechanisms may also regulate mucus secretion and the bronchial microvasculature. The role of this nervous system in health and disease is still uncertain as there are no specific blockers available.
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PMID:Non-adrenergic non-cholinergic neural control of human airways. 242 61

Nerve fibers containing neuropeptide Y (NPY), vasoactive intestinal polypeptide (VIP), substance P (SP), and calcitonin gene-related peptide (CGRP) were seen in the adventitia or at the adventitia-media border of the human temporal artery. Pharmacological experiments on isolated temporal artery segments revealed that NPY potentiated the vasoconstrictor responses to noradrenaline, but had no vasoconstrictor ability or only a small vasoconstrictor ability per se. VIP, peptide histidine methionine 27 (PHM-27), SP, neurokinin A (NKA), and CGRP potently relaxed vessels precontracted by prostaglandin F2 alpha, the relative potency being CGRP greater than SP greater than NKA = VIP = PHM-27. The amount of relaxation varied between 67 and 91% of the prostaglandin F2 alpha-induced contraction. The peptide effects were not antagonized by classic adrenergic or cholinergic blockers, suggesting interactions via separate receptor sites.
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PMID:Localization and effects of neuropeptide Y, vasoactive intestinal polypeptide, substance P, and calcitonin gene-related peptide in human temporal arteries. 243 50

Nerve fibers containing neuropeptide Y, vasoactive intestinal peptide (VIP), substance P (SP), and calcitonin gene-related peptide (CGRP) were seen in the adventitia or at the adventitia-media border of human cerebral arteries obtained during neurosurgical procedures. Radioimmunoassay of human cerebral arteries, removed at autopsy, revealed that the levels of the four peptides did not differ among the major cerebral arteries. There was, however, a gradual decline in peptide concentrations with increasing age of the patients, as measured in the proximal part of the middle cerebral artery. Pharmacological experiments on fresh segments of cerebral (pial) arteries in vitro revealed that neuropeptide Y caused vasoconstriction per se but did not potentiate the contractile response of noradrenaline. VIP, peptide histidine methionine-27 (PHM-27), SP, neurokinin A (NKA), and human CGRP potently relaxed vessels precontracted by prostaglandin F2 alpha, the relative potency being human CGRP greater than SP greater than VIP greater than NKA greater than PHM-27. The amount of relaxation varied between 55% (SP) and 96% (human CGRP) of the prostaglandin F2 alpha-induced contraction. The peptide effects were not antagonized by propranolol, atropine, or cimetidine, suggesting an action that does not involve adrenergic, cholinergic, or histaminergic receptors.
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PMID:Peptide-containing nerve fibers in human cerebral arteries: immunocytochemistry, radioimmunoassay, and in vitro pharmacology. 243 92

Sympathetic and parasympathetic influences on the airway resistance under physiological and pathophysiological conditions have long been known. In recent years, this classical view had to be extended due to mounting evidence of neurocrine and paracrine peptide mediators. The term non-adrenergic non-cholinergic (NANC) nervous system was coined. Besides other effects the non-adrenergic mediators (e.g. VIP and PHI/PHM) give rise to bronchodilation, while the non-cholinergic modulators (SP, neurokinin A, and CGRP) induce bronchospasm. The axon-reflex theory postulates liberation of non-cholinergic peptide substances by afferent C-fibers exposed by bronchial epithelial cell damage as one important cause of bronchial obstruction. In addition to biogenic amines, such peptides as bombesin, leu-encephalin, beta-endorphin, calcitonin, doctrine cells of the bronchial epithelium. Our knowledge of the biological relevance of these mediators is at present very sketchy. Platelet activating factor (PAF) is released by alveolar macrophages, granulocytes, blood vessel endothelium, and platelets. The inhalation of PAF induces bronchospasm in healthy subjects and asthmatics and also prolonged bronchial hyperreactivity. The many factors influencing bronchial reactivity need to be classified by further investigations of the mode of interaction and interdependence of known and new mediators.
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PMID:[The significance of endocrine, neurocrine and paracrine mediators in the regulation of bronchial reactivity]. 268 1

Several peptides synthesized by primary sensory neurons are alpha-amidated at the C-terminal residue, including vasoactive intestinal polypeptide, neurokinin A and substance P, which is also abundant in spinal cord. In pituitary and other tissues, the C-terminal amidation is catalyzed by peptidylglycine alpha-amidating monooxygenase (PAM). In the present study, soluble PAM activity in spinal cord and in primary sensory neurons is quantified and characterized as to cofactor and cosubstrate requirements and substrate specificity.
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PMID:Peptidylglycine alpha-amidating monooxygenase activity in spinal cord, dorsal roots, and dorsal root ganglia of Macaca fascicularis. 276 92

The pathophysiology of Hirschsprung's disease has not been fully elucidated but is known to have a neurogenic basis. In recent years, new neural proteins and peptides have been discovered and our aim in this study was to use immunocytochemistry to investigate their involvement in the neuronal abnormalities associated with this condition. Large bowel samples from 9 children undergoing surgery for Hirschsprung's disease were compared with those taken from 8 children with other gastrointestinal diseases but no aganglionosis. Immunocytochemistry was carried out using antibodies to a wide range of neuron specific proteins and peptides. Examination of sections immunostained for the general neuronal markers, protein gene product 9.5, neuron specific enolase and neurofilament triplet proteins, allowed rapid identification of aganglionic segments. Nerves containing vasoactive intestinal polypeptide/peptide histidine methionine (VIP/PHM), galanin, substance P, somatostatin, met-enkephalin or calcitonin gene-related peptide (CGRP) showed a marked reduction in all layers of the aganglionic bowel. However, scattered VIP/PHM immunoreactive fibres were also found in the hypertrophied nerve bundles. In contrast with these reduced peptide-containing nerves, fibres displaying NPY immunoreactivity showed a marked increase in all aganglionic segments, particularly in the circular muscle where few are found normally. Our findings shed further light on the neurobiology of aganglionic bowel and suggest that immunostaining of neural proteins and the peptide NPY can aid rapid histopathological diagnosis of congenital aganglionosis.
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PMID:Increased neuropeptide Y-immunoreactive innervation of aganglionic bowel in Hirschsprung's disease. 311 47

The innervation of the sphincter of Oddi (SO) has been extensively studied experimentally, but human studies have not been published, which is why this study was undertaken. Biopsies, taken by gastroscopy-biopsy forceps from duodenal epithelium of the papilla of Vater and from ampullary epithelium after sphincterotomy, did not demonstrate nerves and could not be used for studying SO innervation. Therefore SO specimens were obtained from brain-dead organ donors (N = 5) and from autopsies (N = 14). By staining with a myelin marker S-100, a rich network of nerves was demonstrated in SO. The occurrence of vasoactive intestinal polypeptide (VIP), peptide histidine-isoleucine (PHI) (or its immunologically similar human equivalent peptide histidine methioninamide, PHM), neuropeptide Y, calcitonin gene-related peptide (CGRP), galanin, substance P, enkephalin, bombesin, and somatostatin were studied by immunohistochemical technique. SO demonstrated immunoreactivity for VIP, PHI (PHM), neuropeptide Y, CGRP, galanin, somatostatin, substance P, and enkephalin, but no immunoreactivity was observed for bombesin. The SO immunoreactivity was similar in specimens from organ donors and from autopsies of victims of violence without pancreatobiliary diseases (N = 3) when the specimens were taken within 48 hr of death. Autopsy specimens of SO from subjects with gallstone disease (N = 5), recurrent pancreatitis (N = 3) or periampullary carcinoma (N = 3) also demonstrated similar immunoreactivity. We conclude that VIP-, PHI- (PHM-), neuropeptide Y-, CGRP-, galanin-, substance P-, somatostatin-, and enkephalin-like immunoreactivity occur in human SO. These neuropeptides may have role in the neural control of human SO function.
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PMID:Peptidergic innervation of human sphincter of Oddi. 831 11

Non-adrenergic, non-cholinergic (NANC) nerve stimulation results in excitation (e.j.p., rebound depolarization, contractions) or inhibition (i.j.p., afterhyperpolarization, relaxations) of the gut. NANC neuronal mechanisms participate in the maintenance of the basal tone and spontaneous activity of the gut. There are however species differences, i.e. both NANC excitation and inhibition are present in the guinea pig and only NANC inhibition in the rat intestine. Substance P-like neuropeptide/s are suggested to be mediators released from excitatory NANC and sensory nerves. The latter are activated by histamine and degenerated by capsaicin. There is evidence in favor of a nitric oxide-like substance rather than ATP, dopamine, GABA and neuropeptides (e.g. VIP, PHI/PHM) as the inhibitory NANC mediator in the gut. TTX, high Mg(2+)-low Ca2+ media, 3,4-diaminopyridine, dipyridamol and adenosine deaminase modulate NANC excitation and inhibition. The NANC excitation is more sensitive than the NANC inhibition to the action of catecholamines, reserpine, 6-hydroxydopamine, chymotrypsin, prednisolon, bacitracin, opioids, free oxygen species and low concentration of local anesthetics.
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PMID:NANC transmission in intestines and its pharmacological modulation. 839 Nov 98


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