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)

The purpose of this review is to present current knowledge regarding purinergic receptors and their subtypes. The main endogenous ligans for these receptors are adenosine and ATP which are released from cells and neurons under various pathophysiological conditions, and adenine nucleotides which are released as contransmiters together with noradrenaline, acetylcholine and substance P. Purinergic receptors which are present in various tissues and mediate numerous physiological effects can be divided into two main groups, P1 (for adenosine) and P2 (for adenine nucleotides) receptors. Both these types are further divided into subtypes. P1 receptors are better characterized than P2 receptors whose classification must be regarded as tentative rather than definitive. P1 receptors are named according to their natural ligand adenosine as A1, A2a, A2b, A3 and possibly A4 receptors. Their characteristics are summarized in tables which also present the main selective agonists and antagonists of their receptors. Since the classification of P2 receptors is still tenative, their nomenclatue does not follow the exact rules which are provided by IUPHAR. P2 receptors are subdivided into these subtypes: P2X, P2Y, P2U, P2T, P2Z and P2D. The article also lists the main agonists and antagonists for these receptors. The introduction of new selective agonists and antagonists not only helps to classify various receptors subtypes of purinoceptors but it also has a big therapeutic potential for various diseases.
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PMID:[Purinergic receptors--nomenclature and classification of types and subtypes]. 758 17

Calcium signaling in fura-2 acetoxymethyl ester-loaded enteric glia was investigated in response to neuroligands; responses to ATP were studied in detail. Carbachol (1 mM), glutamate (100 microM), norepinephrine (10 microM), and substance P (1 microM) did not increase the intracellular calcium concentration ([Ca2+]i) in cultured enteric glia. An increasing percentage of glia responded to serotonin (4%; 100 microM), bradykinin (11%; 10 microM), and histamine (31%; 100 microM), whereas 100% of glia responded to ATP (100 microM). ATP-evoked calcium signaling was concentration dependent in terms of the percentage of glia responding and the peak [Ca2+]i achieved; responses were pertussis toxin insensitive. Based on responsiveness of enteric glia to purinergic agonists and peak [Ca2+]i evoked, ATP = UTP > ADP > beta, gamma-methyleneadenosine 5'-triphosphate >> 2-methylthioadenosine 5'-triphosphate = alpha,beta-methyleneadenosine 5'-triphosphate = AMP = adenosine, suggesting a glial P2U receptor. Depletion of D-myo-inositol 1,4,5-trisphosphate-sensitive calcium stores by thapsigargin (10 microM) abolished glial responses to ATP. Similarly, calcium responses were decreased 92% by U-73122 (10 microM), an inhibitor of phospholipase C, and 93% by the phorbol ester phorbol 12-myristate 13-acetate (100 nM), an activator of protein kinase C. Thus, cultured enteric glia can respond to neurotransmitters with increases in [Ca2+]i. Our data suggest that glial responses to ATP are mediated by a P2U receptor coupled to activation of phospholipase C and release of intracellular calcium stores.
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PMID:Enteric glia exhibit P2U receptors that increase cytosolic calcium by a phospholipase C-dependent mechanism. 859 30

The frequency of spontaneous action potentials of locus coeruleus neurons was recorded extracellularly in pontine slices of the rat brain. The adenosine 5'-triphosphate (ATP) analogues alpha,beta-methylene ATP (alpha,beta-meATP) and 2-methylthio ATP increased the firing rate with a similar potency, while uridine 5'-triphosphate (UTP) was inactive. Diadenosine 5'-pentaphosphate (Ap5A), diadenosine 5'-tetraphosphate (Ap4A) and diadenosine 5'-triphosphate (Ap3A) all facilitated the firing. When equimolar concentrations were compared, Ap5A had the largest effect followed by Ap4A and Ap3A. Suramin markedly inhibited responses to alpha,beta-meATP and 2-methylthio ATP; the effect of Ap4A was only slightly depressed by suramin. Pyridoxalphosphate-6-azophenyl-2,4-disulfonic acid (PPADS) strongly antagonized alpha, beta-meATP, but failed to alter the effects of 2-methylthio ATP and Ap4A. Reactive blue 2 weakly antagonized alpha,beta-meATP and did not interfere with 2-methylthio ATP and Ap4A. Moreover, suramin depressed responses to (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartic acid (NMDA), but not to substance P. PPADS failed to affect the AMPA- and NMDA-induced increases in firing. Hence, locus coeruleus neurons may possess receptors for adenosine nucleotides (P2X and P2Y purinoceptors) and dinucleotides (P2D purinoceptors); receptors for uridine nucleotides (P2U purinoceptors or pyrimidinoceptors) are probably absent.
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PMID:Pharmacological characterization of P2 purinoceptor types in rat locus coeruleus neurons. 898 62

Rat submandibular salivary gland acinar cells were transfected by CaPO4 precipitation using a plasmid containing a replication-defective simian virus (SV40) genome. Out of 27 clonal cell lines, two were shown to have moderate to high levels of cytodifferentiation and salivary gland acinar cell function. Functional studies with the two cell lines indicated that the beta-adrenergic agonist, isoproterenol, vasoactive intestinal peptide, and prostaglandin E1 were effective activators of intracellular cyclic AMP production. Epinephrine, norepinephrine, phenylephrine, acetylcholine, and P2U-purinoceptor agonists were effective in increasing inositol phosphate production and intracellular free calcium levels, whereas substance P was without effect. Utilizing indirect immunofluorescence analysis, both cell lines were shown to express glutamine/glutamic acid-rich proteins, a submandibular acinar cell specific secretory protein family. Electron microscopic evaluation documented the maintenance of tripartite junctional complexes, cellular polarization, and the presence of moderate amounts of secretory granules and rough endoplasmic reticulum. The two cell lines had doubling times of 25 h.
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PMID:Development and characterization of SV40 immortalized rat submandibular acinar cell lines. 911 24

The purpose of this investigation was to develop well-differentiated rat parotid and submandibular acinar cell lines. Acinar cells dissociated from rat parotid and submandibular glands were grown on Mitomycin C-treated 3T3 fibroblasts or Matrigel in primary culture and transfected by CaPO4 precipitation using a plasmid containing a replication-defective simian virus (SV40) genome. Cytokeratin analysis via indirect immunofluorescence and receptor mediated changes in intracellular calcium and cyclic AMP were assessed and used for the identification and selection of immortalized epithelial cells. Of the more than 60 clonal cell lines, four retained moderate to high levels of acinar differentiation through >60 passages. Ultrastructurally, there were tripartate junctional complexes and moderate amounts of rough endoplasmic reticulum and secretory granules. Functional studies indicated that beta-adrenoceptors, vasoactive intestinal peptide, and prostaglandin E1 were effective activators of intracellular cyclic AMP production in all cell lines. Alpha-adrenoceptors, muscarinic cholinoceptors, and P2U-purinoceptor agonists were effective in increasing intracellular inositol phosphate production and free calcium levels whereas substance P was ineffective. These data document the utility of the SV40 plasmid in immortalizing rat parotid and submandibular acinar cells that retain most of the features of acinar differentiation.
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PMID:Development and characterization of immortalized rat parotid and submandibular acinar cell lines. 982 93

The aims of this study were to characterize G protein-coupled receptors endogenously expressed by ECV304 human endothelial cells, and to determine the utility of this transformed cell line as a vehicle for the expression of cloned receptors. Cellular responses to a broad range of agonists were determined by measuring changes in the intracellular content of second messengers (inositol phosphates and cyclic adenosine monophosphate). These studies identified H1 histamine receptors, P2U-purinoceptors and lysophosphatidic acid receptors which are functionally coupled to phosphoinositidase C. G protein-coupled receptors which bind adenosine (A2 receptor), calcitonin, and adrenaline (beta-adrenoceptor), and markedly stimulate adenylyl cyclase, are also endogenously expressed by ECV304. Agonists which did not stimulate ECV304 cells are: angiotensin II, angiotensin1-7, bombesin, bradykinin, desArg9-bradykinin, carbachol, endothelin-1, neurotensin, serotonin, substance K, substance P, thrombin and vasopressin. The rat Via vasopressin receptor was expressed by lipofection in two antibiotic-resistant clonal lines and expression confirmed by measuring agonist-induced changes in inostol phosphate production. We conclude that the ECV304 cell line is a suitable in vitro system to study the signal transduction pathways of some endogenous G protein-coupled receptors known to modulate endothelial function in vivo. ECV304 is also appropriate for the expression and functional characterization of cloned receptor proteins.
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PMID:Characterization of G protein-coupled receptors expressed by ECV304 human endothelial cells. 983 30

Mechanical activation of the mucosal lining of the colon by brush stroking elicits an intestinal neural reflex and an increase in short circuit current (Isc) indicative of electrogenic chloride ion transport. We tested whether endogenous nucleotides are physiologic regulators of mucosal reflexes that control ion transport. The brush stroking-evoked Isc response in mucosa and submucosa preparations (M-SMP) of rat colon was reduced by the P2Y1 receptor (R) antagonist 2'deoxy-N6-methyl adenosine 3',5'-diphosphate diammonium salt (MRS 2179) and further blocked by tetrodotoxin (TTX). M-SMP Isc responses to serosal application of the P2Y1 R agonist 2-methylthioadenosine-diphosphate (2MeSADP) or the P2Y2/P2Y4 R agonist 5'uridine-triphosphate (UTP) were reduced but not abolished by TTX. The potency profile of nucleotides for increasing Isc was 5'adenosine-triphosphate (ATP; effective concentration at half maximal response [EC50] 0.65 x 10(4) M) congruent with UTP (EC50 1.0 x 10(-4) M) congruent with 2MeSADP (EC50 = 1.60 x 10(-4) M). Mucosal touch and distention-induced Ca2+ transients in submucous neurons were reduced by apyrase and prevented by blocking the P2Y1 R with MRS 2179 and TTX; denervation of the mucosa. It did not occur by touching a ganglion directly. 2MeSADP Ca2+ responses occurred in subsets of neurons with or without substance P (SP) responses. The potency profile of nucleotides on the neural Ca2+ response was 2MeSADP (5 x 10(-7) M) > UTP (6 x 10(-6) M) > ATP (9 x 10(-5) M). The expression of P2Y R immunoreactivity (ir) in nerve cell bodies was in the order of P2Y1 R > P2Y4 R >> P2Y2 R. P2Y1R ir occurred in the cell somas of more than 90% of neuronal nitric oxide synthase, vasoactive intestinal peptide (VIP), calretinin, or neuropeptide Y (NPY)-ir neurons, 78% of somatostatin neurons, but not in calbindin or SP neurons. P2Y2 R ir was expressed in a minority of SP, VIP, NPY, vesicular acetylcholine transporter, and calcitonin gene-related peptide-ir varicose fibers (5-20%) and those surrounding calbindin (5-20%) neurons. P2Y4 ir occurred mainly in the cell somas of 93% of NPY neurons. Reverse transcriptase polymerase chain reaction of the submucosa demonstrated mRNA for P2Y1R, P2Y2, P2Y4, P2Y6, and P2Y12 Rs. Expression of P2Y1, P2Y2, and P2Y4 protein was confirmed by western blots. In conclusion, endogenous nucleotides acting at P2YRs transduce mechanically evoked reflex chloride ion transport in rat distal colon. Nucleotides evoke reflexes by acting primarily at postsynaptic P2Y1 Rs and P2Y4 R on VIP+/NPY+ secretomotor neurons, at P2Y2 Rs on no more than 2% of VIP+ secretomotor neurons, and 2Y2 Rs mainly of extrinsic varicose fibers surrounding putative intrinsic primary afferent and secretomotor neurons. During mucosal mechanical reflexes, it is postulated that P2Y1 R, P2Y2 R, and P2Y4 R are activated by endogenous ATP, UTP, and 5'uridine-diphosphate.
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PMID:Mechanically evoked reflex electrogenic chloride secretion in rat distal colon is triggered by endogenous nucleotides acting at P2Y1, P2Y2, and P2Y4 receptors. 1468 71

Mucus hypersecretion is common in inflammatory and allergic lung disease. Excessive mucus production leads to obstruction of airways and favours bacterial colonization. Advances in understanding the signalling and transduction pathways of mucin gene expression as well as mechanisms of mucin protein production and secretion have defined new therapeutic targets. Conventional therapies include anticholinergics, beta2-adrenoceptor agonists, glucocorticosteroids, mucolytics and macrolide antibiotics. Novel therapeutic approaches are inhibitors of cholinergic nerve activity, tachykinin receptor antagonists, epoxygenase inducers, inhibitors of mucin exocytosis, inhibitors of mucin synthesis and goblet cell hyperplasia, inducers of goblet cell apoptosis and P2Y2 purinoceptor antagonists to inhibit mucin secretion. After providing a short overview on conventional therapies this review will focus on new therapeutic targets.
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PMID:Emerging mucus regulating drugs in inflammatory and allergic lung disease. 1847 98