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)

In spinal cord neurons in anesthetized rats, the role on neurokinin A and neurokinin-2 receptors in the processing of nociceptive information from the knee joint was studied. The specific non-peptide antagonist at the neurokinin-2 receptor, SR48968, its inactive R-enantiomer, SR48965, neurokinin A, substance P and (RS)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), were administered ionophoretically close to neurons with input from the knee joint. SR48968 reduced the effects of exogenous neurokinin A, but not those of exogenous substance P and AMPA, indicating selective blockade of neurokinin-2 receptors. In most neurons with input from the normal knee joint, SR48968 reduced dose-dependently the responses to noxious pressure with applied to the knee, and in approximately 50% of the neurons the responses to innocuous pressure. The administration of SR48968 during the induction of an experimental joint inflammation markedly attenuated the development of inflammation-evoked hyperexcitability. In hyperexcitable neurons with input from the inflamed joint, SR48968 reduced the responses to noxious and innocuous pressure. The relative reduction of the responses was more pronounced than in neurons with input from the normal joint. None of the effects of SR48968 was mimicked by SR48965. These data show that neurokinin-2 receptors are involved in the spinal processing of nociceptive information from the normal joint. Furthermore, neurokinin-2 receptors must be coactivated at an early stage of inflammation, to allow the generation of hyperexcitability. Finally, neurokinin-2 receptors are involved in maintenance of hyperexcitability during inflammation. In summary, spinal neurokinin-2 receptors are important in the generation of pain in the normal and inflamed joint.
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PMID:The role of spinal neurokinin-2 receptors in the processing of nociceptive information from the joint and in the generation and maintenance of inflammation-evoked hyperexcitability of dorsal horn neurons in the rat. 871 96

We studied the biochemical properties of a genetically engineered neurokinin-1 receptor (NK1R) in which two residues lying on the extracellular edge of the fourth transmembrane domain were replaced by equivalently located elements of the neurokinin-2 receptor (G166C, Y167F NK1R mutant). The mutation produced two effects. The first is enhancement of the apparent binding affinity for heterologous tachykinins (substance K and neurokinin B) and for N- or C-terminal modified analogues of substance P, but not for substance P itself, its full-length analogues, and several peptide and nonpeptide antagonists. Only two antagonists, as exceptions, were found to exhibit a diminished affinity for the mutant receptor. The second effect is a shift in NK1R preference for distinct G protein-mediated signaling pathways. NK1R-mediated phosphoinositide hydrolysis was enhanced both in transiently and permanently transfected cells, while stimulation of cAMP accumulation did not change in transient expression experiments and was reduced in permanently expressing cells. The effect of the mutation on ligand affinity was not related to any obvious structural commonality, nor to the selectivity for different neurokinin receptors or the agonistic/antagonistic nature of the ligand. However, all ligands responding to the mutation appear to share the ability to induce phosphoinositide signaling more efficiently than cAMP responses when binding to NK1R. We suggest that the mutation shifts the internal equilibria of different functional forms of NK1R. A theoretical analysis according to a multistate allosteric model suggests that the link between binding and biological changes can result from altered stability constants of substates in the conformational space of the receptor.
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PMID:A mutation changes ligand selectivity and transmembrane signaling preference of the neurokinin-1 receptor. 906 20

To assess whether functional neurokinin receptors exist in the deep dorsal horn of the rat, the actions of the selective neurokinin-1 receptor (NK1R) agonist [Sar9,Met(O2)11]substance P ([Sar9,Met(O2)11]SP), the neurokinin-2 receptor (NK2R) agonists [beta-Ala8]NKA(4-10) and GR64349 and the neurokinin-3 receptor (NK3R) agonist senktide were examined intracellularly in vitro. [Sar9,Met(O2)11]SP (1-4 microM) and senktide (1-2 microM) elicited slow depolarizations (<10 mV) associated with increased synaptic activity and cell firing. [beta-Ala8]NKA(4-10) (10-20 microM) and GR64349 (0.25-10 microM) caused small depolarizations (<2.0 mV) and no firing. Neurons were categorized as either 'tonic' or 'phasic' depending on their firing response to direct current step depolarizations. Tonic neurons, which, unlike phasic neurons, display no spike firing accommodation, generated a significantly larger depolarization to the NK1R and NK3R agonists. The putative contribution of these receptors to primary afferent-mediated synaptic transmission was assessed by testing the NK1R antagonist GR82334 (1 microM), the NK2R antagonist MEN10,376 (1 microM) and the NK3R antagonist [Trp7,beta-Ala8]NKA(4-10) (1 microM) against the dorsal root-evoked excitatory postsynaptic potential (DR-EPSP). GR82334 and [Trp7,beta-Ala8]NKA(4-10) significantly reduced (P < or = 0.05) the duration but not the amplitude of the DR-EPSP. MEN10,376 (1 microM) had no effect on DR-EPSP amplitude or duration. Morphological detail was obtained for seven biocytin-filled deep dorsal horn neurons tested with [Sar9,Met(O2)11]SP. Five neurons responded to the NK1R agonist, and two of these had dorsally directed dendrites into the substantia gelatinosa. The other three [Sar9,Met(O2)11]SP-sensitive neurons had dendrites within deeper laminae. These data support the existence of functional NK1Rs and NK3Rs in the deep dorsal horn which may be involved in mediating sensory afferent inputs from nociceptors.
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PMID:Tachykinin actions on deep dorsal horn neurons in vitro: an electrophysiological and morphological study in the immature rat. 918 56

The relationship between airway mucosal permeability and airway hyperresponsiveness was examined with tachykinins, their selective antagonists, and superoxide dismutase in male Hartley guinea pigs. In animals with ozone-induced airway inflammation, airway hyperresponsiveness and mucosal permeability increased concurrently but there was a time lag before the increase in airway vascular permeability. To study the role of tachykinins in the increases in mucosal permeability and in hyperresponsiveness, we used a neurokinin-receptor antagonist, CP-96345, and a neurokinin-2 receptor antagonist, SR-48968. CP-96345 had no significant effect, but SR-48968 reduced the increase in airway mucosal permeability; their effects on airway hyperresponsiveness were the opposite of their effects on airway permeability. Tachykinins themselves, both substance P and neurokinin A, significantly increased airway mucosal permeability. Superoxide dismutase, a scavenger enzyme of superoxide, reduced the ozone-induced airway hyperresponsiveness. These data suggest that the factors causing airway hyperresponsiveness differ from those that influence mucosal permeability, but it is possible that these pathophysiologic conditions are caused by the same substances or processes.
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PMID:[Airway hyperresponsiveness and airway mucosal permeability]. 921 82

The regulation of striatal cholinergic function by dopamine D1 receptor activation was examined in vivo in urethane-anaesthetized rats with microdialysis probes. Extracellular acetylcholine levels were enhanced by activation of D1 receptors either directly by a striatal application of the D1 receptor agonist (+)-SKF-38393 (3 microM) or indirectly by the release of dopamine evoked by striatal application of neurotensin (0.1 microM) under D2 receptor blockade. SR 144190, a new potent and selective non-peptide neurokinin-2 receptor antagonist (0.03-1 mg/kg, i.p.), dose-dependently reduced the acetylcholine release induced by (+)-SKF-38393 or neurotensin. Furthermore, intrastriatal application of SR 144190 (1 nM) blocked the increase in acetylcholine release induced by the local application of (+)-SKF-38393 (3 microM), neurokinin A (1 microM) or substance P (1 microM). Finally, a role for nitric oxide in mediating the effects of D1 neurokinin-2 receptor activation on acetylcholine release is proposed since local infusion of the competitive inhibitor of nitric oxide synthase, N(G)-monomethyl-L-arginine (0.01-10 microM), blocked the increase in acetylcholine release induced by (+)-SKF-38393 (3 microM), neurotensin (0.1 microM) or neurokinin A (1 microM) without affecting the enhancing effect of the neurokinin-1 agonist septide (0.1 microM).
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PMID:Facilitation of striatal acetylcholine release by dopamine D1 receptor stimulation: involvement of enhanced nitric oxide production via neurokinin-2 receptor activation. 953 21

Two mouse monoclonal antibodies, 11H9.1 and 1G7.10, raised against the COOH-terminus peptide (359-390) of the rat neurokinin-2 receptor, were used to visualize by light and electron microscope immunocytochemistry the distribution of this receptor in adult rat spinal cord. At all spinal levels, immunoreactivity was mainly observed in two narrow crescentic zones bordering the gray matter of the dorsal and ventral horns, and around the central canal. In the light microscope, this labelling was the densest within the outer part of lamina I facing the dorsal column, where it took the form of minute dots and streaks scattered in the neuropil. In the electron microscope, such a localization was exclusively astrocytic and essentially involved astrocytic leaflets, as indicated by the size and irregular shape of the immunostained processes, their location between and around neuronal profiles, and their occasional display of glial filaments. The diaminobenzidine reaction product showed some predilection for the plasma membrane and was occasionally seen at gap junctions of these labelled processes. Many labelled astrocytic leaflets were observed in the immediate vicinity of axon terminals containing large dense-cored vesicles, and around fibres morphologically identifiable as primary afferent, unmyelinated C-fibres. These observations suggest that astrocytic neurokinin-2 receptors could define the effective sphere of neurokinin A neuromodulation in rat spinal cord, via alterations in the regulation of the extracellular environment and glutamate uptake by astrocytes and/or the release of putative astroglial mediators. The astrocyte neurokinin-2 receptors, activated by extrasynaptic neurokinin A, might thus co-operate with neurokinin-1 and neurokinin-3 neuronal receptors in the modulation of nociceptive information.
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PMID:Astroglial distribution of neurokinin-2 receptor immunoreactivity in the rat spinal cord. 957 9

The role of endogenous 5-lipoxygenase products in modulating tachykinergic neurotransmission in guinea pig isolated trachea was investigated. Tachykinin-containing afferent nerve fibers were stimulated with either electrical field stimulation or antidromic stimulation of the right vagus nerve. This resulted in contractions of the isolated caudal trachea and bronchus that could be blocked with either tetrodotoxin or a combination of neurokinin-1 and neurokinin-2 receptor antagonists. The 5-lipoxygenase inhibitor ZD 2138 (1 microM) significantly inhibited these neurally mediated tachykinergic contractions, by approximately 50%, yet had no effect on the contractions evoked by stimulating tachykinergic fibers in an action potential-independent fashion with capsaicin or by exogenously applied neurokinin A. The effect of ZD 2138 on action potential-driven tachykinergic contractions was mimicked by pobilukast, pranlukast, montelukast and zafirlukast, four structurally unrelated antagonists of the cysteinyl leukotriene 1 receptor subtype. Pobilukast had no effect on the tachykinergic contraction in tissues pretreated with ZD 2138. Likewise, ZD 2138 had no effect on the tachykinergic contractions in tissues pretreated with pobilukast. Intracellular electrophysiological recording of the membrane properties of jugular ganglion neurons, the source of tachykinins in the guinea pig trachea/bronchus, demonstrated that leukotriene D4 caused a membrane depolarization of vagal afferent C-fiber neurons and an increase in input impedance, both of which were abolished by zafirlukast. Taken together, these data indicate that in the resting guinea pig isolated trachea/bronchus, endogenous 5-lipoxygenase activity leads to the production of cysteinyl leukotrienes that amplify action potential-dependent release of tachykinins from airway afferent nerve fibers.
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PMID:Inhibition of 5-lipoxygenase diminishes neurally evoked tachykinergic contraction of guinea pig isolated airway. 958 Jun 4

The ligand binding signals to a wide variety of seven transmembrane cell surface receptors are transduced into intracellular signals through heterotrimeric G-proteins. Recently, there have been reports which show diverse coupling patterns of ligand-activated receptors to the members of Gq family alpha subunits. In order to shed some light on these complex signal processing networks, interactions between G alpha q family of G protein and neurokinin-2 receptor as well as muscarinic M1 receptor, which are considered to be new therapeutic targets in asthma, were studied. Using washed membranes from Cos-7 cells co-transfected with different G alpha q and receptor cDNAs, the receptors were stimulated with various concentrations of carbachol and neurokinin A and the agonist-dependent release of [3H]inositol phosphates through phospholipase C beta-1 activation was measured. Differential coupling of G alpha q family of G-protein to muscarinic M1 receptor and neurokinin-2 receptor was observed. The neurokinin-2 receptor shows a ligand-mediated response in membranes co-transfected with G alpha q, G alpha 11 and G alpha 14 but not G alpha 16 and the ability of the muscarinic M1 receptor to activate phospholipase C through G alpha q/11 but not G alpha 14 and G alpha 16 was demonstrated. Clearly G alpha q/11 can couple M1 and neurokinin-2 receptor to activate phospholipase C. But, there are differences in the relative coupling of the G alpha 14 and G alpha 16 subunits to these receptors.
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PMID:Differential coupling of G alpha q family of G-protein to muscarinic M1 receptor and neurokinin-2 receptor. 987 70

The expression of neurokinin-1 receptors in isolated dorsal root ganglion neurons of adult rats was investigated using substance P covalently bound to a 1.4-nm gold particle. Binding of substance P-gold was determined in neurons after 0.8, 1.8 or 3.8 days under culture conditions. Substance P-gold binding sites were identified in 9.5 +/- 1.8% of the neurons that were cultured for 0.8 days. The proportion of neurons with substance P-gold binding sites increased to 21.5 +/- 3.6% after 1.8 days in culture and returned to the initial values (9.2 +/- 2.1%) after 3.8 days in culture. Binding of substance P-gold was suppressed by co-administration of [Sar9, Met(O2)11] substance P, a specific agonist at the neurokinin-1 receptor, but not by co-administration of [beta-Ala8] Neurokinin A (4-10), an agonist at the neurokinin-2 receptor, and senktide, an agonist at the neurokinin-3 receptor. This indicates that substance P-gold was bound specifically to neurokinin-1 receptors. Double-labelling with RT97, an antibody that selectively labels somata of A-fibres revealed that substance P binding sites were present in small neurons with myelinated and unmyelinated axons. These data show that a proportion of dorsal root ganglion neurons of adult rat in culture exhibit neurokinin-1 receptors. A transient increase in the proportion of neurons expressing neurokinin-1 receptors after 1.8 days in culture suggests that the expression of neurokinin-1 receptors is subjected to regulation.
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PMID:Expression of neurokinin-1 receptors on cultured dorsal root ganglion neurons from the adult rat. 1021 69

Both tachykinins and leukotrienes (LTs) have been demonstrated to be the mediators for hyperpnea-induced bronchoconstriction (HIB) of guinea pigs. We tested the hypothesis that leukotrienes modulate HIB indirectly by triggering tachykinin release. Ninety nine young guinea pigs were divided into four groups: control; LTC4; FPL 55712 (a LT receptor antagonist); and MK-886 (an inhibitor of LT synthesis). Each animal was anesthetized, cannulated, paralyzed, and artificially ventilated. The protocol included the baseline, hyperpnea, and recovery periods. Thus, animals in each group were further divided into three subgroups: baseline; recovery-3 min; and recovery-8 min. We measured dynamic respiratory compliance (Crs), forced expiratory volume in 0.1 s (FEV0.1) and maximal expiratory flow at 30% total lung capacity (Vmax30), as well as determined substance P (SP) and LT levels in plasma and bronchoalveolar lavage (BAL) during either the baseline or the recovery (3 or 8 min) period. Hyperpnea caused decreases in Crs, FEV0.1 and Vmax30, indicating HIB, in the control group at 3 min and 8 min of the recovery period. Both FPL 55712 and MK-886 significantly attenuated HIB. In the control group, hyperpnea caused significant increases in SP and LT levels in both plasma and BAL. These increases in SP levels were significantly suppressed, however, by FPL 55712 and MK-886. Compared to the control group, infusion of LTC4 did not significantly alter either HIB, SP or LT levels in most cases. An additional group of 24 animals treated with neurokinin-2 receptor antagonist, SR 48968, demonstrated that SR 48968 significantly suppressed hyperpnea-induced increases in plasma, but not in BAL, LT levels. Since FPL 55712 and MK-886 first suppress LT activities, these results suggest that suppressed LT activities attenuate HIB indirectly via reducing tachykinin release.
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PMID:Mediators in hyperpnea-induced bronchoconstriction of guinea pigs. 1059


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