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)

1. In the presence of atropine (1 microM), guanethidine (3 microM), indomethacin (3 microM), apamin (0.1 microM) and L-nitroarginine (L-NOARG, 30 microM), electrical field simulation (EFS) produced a nonadrenergic, noncholinergic (NANC) excitatory junctional potential (e.j.p.), action potentials and contraction of the circular muscle of the guinea-pig proximal duodenum, recorded by the single sucrose gap technique. 2. The selective tachykinin (TK) NK1 receptor antagonist, GR 82,334 (30 nM-3 microM) produced a concentration-dependent inhibition of the EFS-evoked NANC e.j.p. and contraction. Similarly, the selective NK2 receptor antagonists, MEN 10,627 (30 nM-3 microM) and GR 94,800 (100 nM-10 microM), both produced a concentration-dependent inhibition of the EFS-evoked NANC e.j.p. and contraction. GR 82,334 inhibited the electrical and mechanical NANC responses to EFS in an almost parallel manner, while MEN 10,627 and GR 94,800 were more effective in inhibiting the mechanical than the electrical response to EFS. 3. Activation of the NK1 or NK2 receptor by the selective agonists, [Sar9]substance P (SP) sulphone and [beta Ala8]neurokinin A (NKA) (4-10), respectively (0.3 microM each), produced depolarization, action potentials and contractions. GR 82,334 selectively inhibited the responses to [Sar9]SP sulphone, without affecting the responses to [beta Ala8]NKA (4-10). MEN 10,627 and GR 94,800 inhibited or abolished the responses to [beta Ala8]NKA (4-10), without affecting the responses to [Sar9]SP sulphone. 4. Nifedipine (1 microM) abolished the action potentials and contraction produced either by EFS or by the TK receptor agonists [Sar9]SP sulphone or [beta Ala8]NKA (4-10). 5. In the presence of nifedipine, the NANC e.j.p. produced by EFS was biphasic: in the majority of strips tested (21 out of 29) an early fast phase of depolarization was followed by a second slow component. The combined administration of GR 82,334 and GR 94,800 (3 microM each) reduced both components, the slow phase being inhibited to a greater extent than the fast phase. 6. The P2 purinoreceptor antagonist, suramin (100 microM) reduced the fast phase of the e.j.p. produced by EFS in the presence of nifedipine, without affecting the slow phase. The combined administration of suramin, GR 82,334 and GR 94,800 produced a nearly complete blockade of the e.j.p. produced by EFS in the presence of nifedipine. 7. When tested in the absence of apamin and L-NOARG, EFS induced a NANC inhibitory junction potential (i.j.p.) followed by an e.j.p., and the selective P2Y receptor agonist, adenosine-5'-O-(2-thiodiphosphate) (ADP beta S, 10 microM), produced membrane hyperpolarization. After addition of apamin and L-NOARG, the ij.p. was blocked, and EFS produced a pure NANC e.j.p.; ADPPS produced depolarization, action potentials and contraction.8. Suramin (100 microM) blocked the depolarization, action potentials and contractions produced by ADP beta S in the presence of apamin and L-NOARG, without affecting the responses produced by the NK1receptor agonist, [Sar9}SP sulphone.9. We conclude that NK1 and NK2 receptors cooperate in producing NANC excitation and contraction of the circular muscle in the guinea-pig proximal duodenum. Activation of either TK receptor produces membrane depolarization and both receptors contribute to generate action potentials which are essential for producing muscle contraction, via nifedipine-sensitive calcium channels. It appears that endogenous ATP chiefly acts as an inhibitory transmitter but, after blockade of NANC inhibitory mechanism(s),ATP may act as a fast signalling excitatory transmitter.
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PMID:Evidence that tachykinin NK1 and NK2 receptors mediate non-adrenergic non-cholinergic excitation and contraction in the circular muscle of guinea-pig duodenum. 754 17

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

Blood vessels in the anterior region of the knee joint of anaesthetised rabbits showed a biphasic response to the electrical stimulation (10 Hz, 1 ms width, 10 V amplitude) of nerve fibres supplying the knee, as measured by laser Doppler flowmetry. The response consisted of vasoconstriction during nerve stimulation followed by a prolonged dilatation. The vasoconstrictor response was mediated by noradrenaline acting mainly via alpha 1-adrenoceptors as it was substantially reduced by close intra-arterial injection of the alpha-adrenergic antagonist phentolamine (approximately 50% reduction) and the selective alpha 1-adrenergic antagonist prazosin (approximately 50% reduction) but not by the alpha 2-antagonist rauwolscine. Further studies involving prolonged (2-hour) close intra-arterial infusion of prazosin gave a approximately 50% reduction of the constrictor response with a concentration of 10(-5) M and approximately 95% reduction when the concentration was raised to 10(-4) M. At the higher prazosin concentration responses to close intra-arterial injection of the alpha 1-agonist phenylephrine were substantially reduced but responses to the alpha 2-agonists clonidine and UK-14304 were not significantly influenced. Infusions of the alpha 2 antagonist CH 38083 failed to inhibit nerve-mediated vasoconstriction at 10(-5) or 10(-4) M. There did not appear to be a purinergic component, as the constrictor response was unaffected by the P2X desensitiser alpha,beta-methylene adenosine 5'-triphosphate. The dilator response appeared to be mediated principally by substance P (presumably released from sensory C fibers) as it was substantially reduced by intraarticular injection of substance P antagonist D-Pro4D-Trp7,9,10-SP(4-11).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nerve-mediated responses of blood vessels in the rabbit knee joint. 809 96

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

By using selective tachykinin NK1 and NK2 receptor antagonists and agonists, we studied the excitatory non-adrenergic non-cholinergic transmission to the circular muscle of the corpus of guinea-pig stomach by the sucrose-gap method. After elimination of inhibitory junction potentials by apamin (0.1 microM), L-nitroarginine (30 microM) and tetraethylammonium (10 mM), electrical field stimulation (10 Hz) in the presence of atropine (1 microM) and nifedipine (1 microM) evoked a pure excitatory junction potential and contraction. The selective tachykinin NK2 receptor antagonist, MEN 11420, concentration-dependently inhibited the non-adrenergic non-cholinergic excitatory junction potential (EC50=0.09 microM) and contraction (EC50=0.04 microM) evoked by electrical field stimulation. On the other hand, the selective NK1 receptor antagonist GR 82334 (3 microM) only slightly (by about 30%) inhibited the excitatory junction potential while leaving the contraction unaffected. The combined administration of GR 82334 (1 microM) and MEN 11420 (0.3 microM) produced an additive inhibition of the excitatoryjunction potential, significantly larger than that produced by each antagonist alone. In the presence of both GR 82334 (1 microM) and MEN 11420 (0.3 microM), the P2 purinoreceptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (30 microM) remarkably inhibited the fast component of the excitatory junction potential. In the presence of atropine (1 microM), indomethacin (3 microM) and guanethidine (3 microM) either the selective NK2 receptor agonist, [betaAla8]neurokinin A (4-10) (0.01 microM), or the selective NK1 receptor agonist, [Sar9]substance P sulfone (0.3 microM), produced tetrodotoxin-(1 microM) and nifedipine-(1 microM) resistant depolarization and contraction. The [Sar9]substance P sulfone (0.3 microM)-induced contraction, but not that induced by [betaAla8]neurokinin A (4 10) (0.01 microM), was potentiated by apamin (0.1 microM) plus L-nitroarginine (30 microM). In the presence of atropine (1 microM), indomethacin (3 microM), guanethidine (3 microM), apamin (0.1 microM) and L-nitroarginine (30 microM), the selective tachykinin NK2 and NK1 receptor agonists, [betaAla8]neurokinin A (4-10) and [Sar9]substance P sulfone, both produced a concentration-dependent depolarization and contraction of the circular muscle. MEN 11420 inhibited the responses to [[Ala8]neurokinin A (4-10) without affecting the responses to [Sar9]substance P sulfone, while GR 82334 inhibited the responses to [Sar9]substance P sulfone but not that to [betaAla8]neurokinin A (4-10). These data provide evidence that tachykinin NK2 receptors predominantly mediate the non-adrenergic non-cholinergic excitatory transmission to the circular muscle of the corpus of guinea-pig stomach. In addition, after blocking the non-adrenergic non-cholinergic inhibitory junction potential by apamin, L-nitroarginine and tetraethylammonium, the fast component of the non-adrenergic non-cholinergic excitatory junction potential could be mediated by adenosine triphosphate.
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PMID:Tachykinin NK1 and NK2 receptors mediate non-adrenergic non-cholinergic excitatory neuromuscular transmission in the guinea-pig stomach. 928 63

The P2X3 receptor subunit, a member of the P2X family of ATP-gated ion channels, is almost exclusively localized in sensory neurons. In the present study, we sought to gain insight into the role of P2X3 and P2X3-containing neurons in sensory transmission, using immunohistochemical approaches. In rat dorsal root ganglia (DRG), P2X3-immunoreactivity (-ir) was observed in small- and medium-sized neurons. Approximately 40% of DRG neuronal profiles in normal rats contained P2X3-ir. In rats that had received neonatal capsaicin treatment, the number of P2X3-positive neurons was decreased by approximately 70%. Analysis of the colocalization of P2X3-ir with cytochemical markers of DRG neurons indicated that approximately 94% of the P2X3-positive neuronal profiles were labelled by isolectin B4 from Bandeiraea simplicifolia, while only 3% contained substance P-ir, and 7% contained somatostatin-ir. In dorsal horn of rat spinal cord, P2X3-ir was observed in the inner portion of lamina II and was reduced subsequent to dorsal rhizotomy, as well as subsequent to neonatal capsaicin treatment. Finally, P2X3-ir accumulated proximal to the site of sciatic nerve ligation, and was seen in nerve fibres in skin and corneal epithelium. In summary, our results suggest that P2X3 is expressed by a functionally heterogeneous population of BSI-B4-binding sensory neurons, and is transported into both central and peripheral processes of these neurons.
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PMID:P2X3 is expressed by DRG neurons that terminate in inner lamina II. 982 60

Epithelial cells were isolated from rat trachea by incubation of the organ in a calcium-free medium. The intracellular concentration of calcium ([Ca(2+)](i)) was measured with the calcium-sensitive fluorescent dye fura2. In resting conditions, the cells maintained a low [Ca(2+)](i) in spite of the presence of millimolar concentration of calcium in the incubation medium. These cells had retained intracellular stores of calcium which were emptied after exposure of the cells to thapsigargin, an inhibitor of intracellular calcium ATPases. Substance P (125 nM) transiently increased 2.5-fold the [Ca(2+)](i). ATP (1 mM) doubled the [Ca(2+)](i) after a few seconds and further induced a sustained increase of the [Ca(2+)](i). Coomassie blue fully blocked the response to ATP and extracellular magnesium only inhibited the delayed response to ATP. Among purinergic analogs, only benzoyl-ATP (Bz-ATP), an agonist on P2X ionotropic purinergic receptors, reproduced the response to ATP. UTP and 2-methylthioATP (two agonists on P2Y metabotropic purinergic receptors) transiently increased the [Ca(2+)](i). Thapsigargin, ATP and Bz-ATP increased the uptake of extracellular calcium. RT-PCR analysis revealed that two metabotropic receptors (P2Y(1) and P2Y(2)) and two ionotropic receptors (P2X(4) and P2X(7)) were expressed by the cells present in the suspension. It is concluded that purinergic agonists can modulate the response of rat tracheal epithelial cells by several mechanisms. The activation of metabotropic receptors should mobilize intracellular IP(3)-sensitive calcium pools. The activation of the ionotropic receptors should not only open a non-specific cation channel leading to the entry of calcium but should also induce the formation of pores in cells expressing the P2X(7) receptors, which could be deleterious to these cells.
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PMID:Regulation by P2 agonists of the intracellular calcium concentration in epithelial cells freshly isolated from rat trachea. 1044 26

The P2X(3) receptor is an ATP-gated ion channel predominantly expressed in nociceptive neurons from the dorsal root ganglion. P2X(3) receptor channels are highly expressed in sensory neurons and probably contribute to the sensation of pain. Kinetics of P2X(3) currents are characterized by rapid desensitization (<100 ms) and slow recovery (>20 s). Thus, any mechanism modulating rate of desensitization and/or recovery may have profound effect on susceptibility of nociceptive neurons expressing P2X(3) to ATP. Here we show that currents mediated by P2X(3) receptor channels and the heteromeric channel P2X(2/3) composed of P2X(2) and P2X(3) subunits are potentiated by the neuropeptides substance P and bradykinin, which are known to modulate pain perception. The effect is mediated by the respective neuropeptide receptors, can be mimicked by phorbol ester and blocked by inhibitors of protein kinases. Together with data from site-directed mutagenesis our results suggest that inflammatory mediators sensitize nociceptors through phosphorylation of P2X(3) and P2X(2/3) ion channels or associated proteins.
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PMID:Inflammatory mediators potentiate ATP-gated channels through the P2X(3) subunit. 1126 91

In this study we have characterized the role of sensory fibers and of the sensory peptides, neurokinin A (NKA) and calcitonin gene-related peptide (CGRP), on the contractile responses evoked by single pulse electrical field stimulation (EFS) in the hamster urinary bladder. EFS of the hamster isolated urinary bladder produced twitch contractions which were unaffected by atropine but abolished by tetrodotoxin. The P2 purinoreceptor antagonist PPADS (30 microM) inhibited twitches by 66+/-4% on its own and by 78+/-3% in the presence of atropine. The selective tachykinin NK2 receptor antagonist nepadutant produced a slight but consistent reduction of twitch amplitude (-21+/-3%) at 1 microM. Addition of nepadutant to atropine and PPADS did not further increase their inhibitory effect. The application of hCGRP (10-300 nM) produced a concentration-dependent inhibition of twitches (Emax -38+/-3%, EC50=12 nM) and a small reduction of tone (0.5+/-0.09 mN). Similar effects were obtained with capsaicin (0.1-10 microM) which inhibited EFS-evoked contractions with an EC50 of 100.0 nM and a maximal effect of 34+/-4% inhibition at 1 microM. Under submaximal parameters of stimulation NKA (10 nM) increased the amplitude of twitches by 45+/-6% and produced a concentration-dependent tonic contraction (EC50=55.9 nM). The CGRP1 receptor subtype antagonist, hCGRP(8-37), increased by 29+/-8% the EFS-evoked contractions and significantly reduced the response to 0.1 microM CGRP. Capsaicin (10 microM) increased both CGRP-LI and NKA-LI release from superfused slices of hamster urinary bladder by about sixfold and by about 70%, over baseline, respectively. A second application of capsaicin was ineffective, indicating a complete desensitization of sensory nerve efferent function. In the hamster urinary bladder the sensory neuropeptides NKA and CGRP are co-released by sensory fibers after stimulation either by EFS or capsaicin. However, the role of CGRP appears functionally predominant.
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PMID:The role of sensory neuropeptides in motor innervation of the hamster isolated urinary bladder. 1152 Nov 67

An intricate surveillance network consisting of enteroendocrine cells, immune cells and sensory nerve fibres monitors the luminal and interstitial environment in the alimentary canal. Functional bowel disorders are characterized by persistent alterations in digestive regulation and gastrointestinal discomfort and pain. Visceral hyperalgesia may arise from an exaggerated sensitivity of peripheral afferent nerve fibres and/or a distorted processing and representation of gut signals in the brain. Novel strategies to treat these sensory bowel disorders are therefore targeted at primary afferent nerve fibres. These neurons express a number of molecular traits including transmitters, receptors and ion channels that are specific to them and whose number and/or behaviour may be altered in chronic visceral pain. The targets under consideration comprise vanilloid receptor ion channels, acid-sensing ion channels, sensory neuron-specific Na(+) channels, P2X(3) purinoceptors, 5-hydroxytryptamine (5-HT), 5-HT(3) and 5-HT(4) receptors, cholecystokinin CCK(1) receptors, bradykinin and prostaglandin receptors, glutamate receptors, tachykinin and calcitonin gene-related peptide receptors as well as peripheral opioid and cannabinoid receptors. The utility of sensory neuron-targeting drugs in functional bowel disorders will critically depend on the compounds' selectivity of action for afferent versus enteric or central neurons.
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PMID:Gastrointestinal afferents as targets of novel drugs for the treatment of functional bowel disorders and visceral pain. 1169 40

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