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)

Following spinal cord transection there occurred decreases in Km and Vmax of glutamate decarboxylase (GAD) both above and below the lesion, and an initial decrease in the concentration of GABA. Concomitantly, there was a gradual decrease in presynaptic inhibition. Eight to 12 weeks after spinal cord transection, Km and Vmax for GAD returned to control values, but the GABA content of the spinal cord below the lesion increased significantly and presynaptic inhibition became maximally depressed. These results suggested that during the chronic phase of spinal cord injury there is a decrease in release of GABA, the interneuronal inhibitory neurotransmitter which mediates presynaptic inhibition. Diazepam, a GABA enhancer, increased presynaptic inhibition in acute and chronic spinal cats, this being accompanied by a reduction in somatic muscular spasticity. The degree of this enhancement by diazepam, however, is attenuated with gradual loss of presynaptic inhibition. In the acute cat, a conditioning volley applied to cutaneous afferents blocked the inhibition of the monosynaptic response to extensor motoneurones. In contrast, in chronic spinal cats (eight to 12 weeks), the duration of complete blockade was markedly reduced and was followed by a prolonged period which cutaneous nerve stimulation potentiated the monosynaptic discharge. Similar to GABA, there also occurred an increase of substance P below the level of the lesion. Other neurotransmitters (e.g., norepinephrine, serotonin) accumulated above and disappeared below the transection level. Although somatic msucular spasticity appears to be, to some extent, due to GABA dysfunction in the spinal cord, alterations in "normal" functioning of other neurotransmitters and the loss of supraspinal control also contribute to this state.
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PMID:Correlation of changes in the GABA-ergic system with the development of spasticity in paraplegic cats. 51 79

We studied the effects of modification of duration of seizures induced by electroconvulsive stimuli (ECS) on the changes in concentration of neuropeptide Y (NPY), neurokinin A (NKA), substance P (SP) and neurotensin (NT)-like immunoreactivity (-LI) in specific rat brain regions. Rats were divided into groups pretreated with saline, indomethacin, flurbiprofen or diazepam prior to either six sham ECSs or six ECSs. After sacrifice by focused microwave irradiation, brains were dissected into frontal cortex, occipital cortex, striatum, hippocampus, pituitary and hypothalamic sections. Peptides were extracted and measured in extract aliquots by specific radioimmunoassays. Repeated ECS increased NPY-LI and NKA-LI in the hippocampus and the occipital cortex. No effect on SP-LI or NT-LI was found. Indomethacin and flurbiprofen had no effect on the tonic seizure time following ECS, and they did not affect the ECS-induced alterations of the brain peptides. Diazepam pretreatment decreased the tonic seizure time following ECS in a dose-dependent manner. However, diazepam did not modify the ECS-induced increase in NPY-LI and NKA-LI concentrations. The results firmly establish that ECS leads to specific peptide increases in discrete rat brain regions and raise the possibility that such changes may not entirely be a consequence of seizures per se.
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PMID:Electroconvulsive stimuli and brain peptides: effect of modification of seizure duration on neuropeptide Y, neurokinin A, substance P and neurotensin. 128 45

Recent studies have demonstrated that Fischer-344 rats from Japanese Charles River Inc. specifically lack dipeptidyl(amino)peptidase IV (DAP IV-negative; EC 3.4.14.5), whereas Fischer-344 rats from sources within the United States (DAP IV-positive) possess normal DAP IV activity. In the present study, plasma from DAP IV-positive rats metabolized substance P (SP) (5.37 +/- 0.25 nmol/min/ml) via the actions of angiotensin-converting enzyme (EC 3.4.15.1) (1.86 +/- 0.50 nmol/min/ml) and DAP IV (2.56 +/- 0.42 nmol/min/ml). DAP IV sequentially converted SP to SP[3-11] and SP[5-11]. The SP[5-11] metabolite was then rapidly hydrolyzed by plasma aminopeptidase M (AmM; EC 3.4.11.2) (36.2 +/- 4.2 nmol/min/ml). In contrast, SP metabolism by plasma from DAP IV-negative rats was less than half that of control animals (2.14 +/- 0.06 nmol/min/ml), due to a complete lack of DAP IV hydrolysis. The absence of DAP IV was not associated with any differences in angiotensin-converting enzyme-mediated hydrolysis of SP (1.45 +/- 0.11 nmol/min/ml) or AmM-mediated hydrolysis of SP[5-11] (37.1 +/- 0.9 nmol/min/ml). Consistent with this deficiency in SP metabolism, SP was more potent in vivo in stimulating salivary secretion in DAP IV-negative rats compared to DAP IV-positive animals. Potentiation was specific in that SP[5-11], an SP fragment resistant to DAP IV, was equipotent in DAP IV-negative and positive animals. SP[5-11]-induced salivary secretion was potentiated in both strains when AmM-mediated hydrolysis was inhibited by amastatin (20 nmol/min, i.v.). These data provide direct evidence for a significant role for DAP IV and AmM in the in vivo processing of SP and active SP metabolites.
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PMID:Dipeptidyl(amino)peptidase IV and aminopeptidase M metabolize circulating substance P in vivo. 137 50

Kinins and substance P have been implicated in the pathogenesis of inflammatory arthritis by virtue of their abilities to induce vasodilation, edema, and pain. The relative biological potencies of these peptides in vivo would depend at least in part upon their rates of catabolism in the joint. We hypothesized that human synovial lining cells may regulate intraarticular levels of kinins and neuropeptides via degradation by cell surface-associated peptidases. We exposed intact human synovial fibroblasts to kinins and substance P, in the presence or absence of specific peptidase inhibitors, and measured the amount of intact substrate remaining and degradation product(s) generated over time. Aminopeptidase M (AmM; EC 3.4.11.2), neutral endopeptidase-24.11 (NEP-24.11; EC 3.4.24.11), and dipeptidyl(amino)peptidase IV (DAP IV; EC 3.4.14.5) were identified on the cell surface of synovial cells. Bradykinin degradation was due entirely to NEP-24.11 (1.39 +/- 0.29 nmol/min per well). Lysylbradykinin was also degraded by NEP-24.11 (0.80 +/- 0.19 nmol/min per well); however, in the presence of phosphoramidon, AmM-mediated conversion to bradykinin (3.74 +/- 0.46 nmol/min per well) could be demonstrated. The combined actions of NEP-24.11 (0.93 +/- 0.15 nmol/min per well) and DAP IV (0.84 +/- 0.18 nmol/min per well) were responsible for the degradation of substance P. AmM (2.44 +/- 0.33 nmol/min per well) and NEP-24.11 (1.30 +/- 0.45 nmol/min per well) were responsible for the degradation of the opioid peptide, [Leu5]enkephalin. The identity of each of the three peptidases was confirmed via synthetic substrate hydrolysis, inhibition profile, and immunological identification. The profiles of peptidase enzymes identified in cells derived from rheumatoid and osteoarthritic joints were identical. These data demonstrate the human synovial fibroblast to be a rich source of three specific peptidases and suggest that it may play a prominent role in regulating peptide levels in the joint.
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PMID:Cultured human synovial fibroblasts rapidly metabolize kinins and neuropeptides. 138 26

In addition to plasma metabolism of substance P (SP) by angiotensin converting enzyme (ACE; EC 3.4.15.1) (less than 1.0 nmol/min/ml), the majority of SP hydrolysis by rat and human plasma was due to dipeptidyl(amino)peptidase IV (DAP IV; EC 3.4.14.5) (3.15-5.91 nmol/min/ml), which sequentially converted SP to SP(3-11) and SP(5-11). In turn, the SP(5-11) metabolite was rapidly hydrolyzed by rat and human plasma aminopeptidase M (AmM; EC 3.4.11.2) (24.2-25.5 nmol/min/ml). The Km values of SP for DAP IV and of SP(5-11) for AmM ranged from 32.7 to 123 microM. In contrast, neurokinin A (NKA) was resistant to both ACE and DAP IV but was subject to N-terminal hydrolysis by AmM (3.76-10.8 nmol/min/ml; Km = 90.7 microM). These data demonstrate differential processing of SP and NKA by specific peptidases in rat and human plasma.
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PMID:Differential processing of substance P and neurokinin A by plasma dipeptidyl(amino)peptidase IV, aminopeptidase M and angiotensin converting enzyme. 172 23

The effects of gamma-aminobutyric acid (GABA) and other drugs which interact with GABA receptors were studied on a reflex of slow time course in the spinal cord preparation isolated from the neonatal rat. A single shock to a dorsal root (L3-L5) elicited a stereotyped series of reflexes, consisting of fast and slow components, recorded from the contralateral ventral root of the corresponding segment. The slow component, i.e. the contralateral slow ventral root potential (v.r.p.) had a time-to-peak of 2-5 s and lasted 20-30 s. Bath-application of GABA (5-20 microM) or muscimol (0.05-0.5 microM) caused a decrease in the amplitude of the contralateral slow v.r.p. without producing any change in the d.c. potential recorded from the ventral root. The monosynaptic reflex recorded from the ipsilateral ventral root was not changed by the drugs at these concentrations. Diazepam (0.1-1 microM) potentiated the depolarizing response of the dorsal root to GABA and markedly depressed the contralateral slow v.r.p. Neither the d.c. potential of the ventral root nor the dorsal root was changed by diazepam. The monosynaptic reflex was also unaffected by the drug. Bicuculline (1 microM) suppressed the GABA-induced depolarization recorded from the dorsal root whilst it markedly potentiated the contralateral slow v.r.p. Baclofen at concentrations from 0.01 to 0.1 microM reduced the contralateral slow v.r.p. The inhibitory action of baclofen on the contralateral slow v.r.p. was more marked than on the monosynaptic reflex. 7 The depolarization of the ventral root induced by a brief application of substance P (SP) was depressed by muscimol, diazepam and baclofen, whereas the depolarization was potentiated by bicuculline. 8 The present results suggest that an intraspinal GABAergic inhibitory mechanism plays a role in the modulation of certain slow spinal reflexes. They also support the hypothesis that SP released from certain primary afferent fibres is a neurotransmitter involved in the contralateral slow v.r.p.
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PMID:GABAergic modulation of a substance P-mediated reflex of slow time course in the isolated rat spinal cord. 243 59

Vasoactive peptides contain a high proportion of proline residues which make them resistant to hydrolysis by many peptidases. However, post proline cleaving enzyme (PPCE; EC 3.4.21.26), a proline specific endopeptidase which specifically hydrolyzes internal peptide bonds on the carboxyl side of proline residues, has been shown to inactivate numerous vasoactive peptides including angiotensins, kinins, substance P, vasopressin and oxytocin. In order to determine whether PPCE could be involved in vascular metabolism of vasoactive peptides, we carried out localization and characterization studies of PPCE-like activity in hog aorta and mesenteric artery. PPCE was assayed fluorometrically at pH 7.0 using the specific PPCE substrate CBZ-Gly-Pro-4-methyl-coumarinylamide. The subcellular distribution of vascular PPCE was essentially the same as that of the cytosolic marker enzyme lactic dehydrogenase (LDH). PPCE was enriched six-fold in the cytosolic fraction (11.4 +/- 2.7 units/mg) and unlike the plasma membrane-bound proline specific exopeptidase dipeptidyl-(amino)peptidase IV (DAP IV; EC 3.4.14.5), little or no activity could be detected in the microsomal or plasma membrane fractions. Similar to PPCE characterized from other sites, vascular PPCE was stabilized and activated by dithiothreitol and EDTA, and inhibited by DFP, p-chloromercuriphenyl sulfonic acid, L-1-tosylamido-2-phenylethylchloromethyl ketone, Cu++, Ca++, and Zn++. Vascular PPCE was unaffected by inhibitors of trypsin and kallikrein (Aprotinin, ABTI), aminopeptidase M (bestatin, amastatin), neutral endopeptidase (phosphoramidon), angiotensin I converting enzyme (captopril) or carboxypeptidase N (MERGETPA). These data demonstrate that PPCE is present in vascular endothelium and/or smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vascular, post proline cleaving enzyme: metabolism of vasoactive peptides. 354 18

The intrathecal (i.t.) administration of morphine inhibits nociceptive motor responses and activity in ascending axons evoked by stimulation of nociceptive afferent nerve fibers (nociceptive sensory response) in the rat. The i.t. administration of cholecystokinin octapeptide and ceruletide inhibits nociceptive motor responses, but does not affect ascending nociceptive activity. This shows that drug-induced depression of nociceptive motor responses is not always associated with depression of the nociceptive sensory response of the spinal cord. The microiontophoretic application of substance P excites single dorsal horn neurons that respond to noxious stimulation, whereas the i.t. administration of substance P inhibits both nociceptive motor and sensory responses. Thus, the results obtained from the i.t. administration of a drug may differ from those obtained from its application to single spinal neurons. Diazepam inhibits spinal reflexes and may reduce pain sensation in humans. To assess whether a spinal action is involved in the pain-relieving effect of diazepam, experiments were carried out on spinalized rats in which activity evoked by the stimulation of nociceptive and nonnociceptive afferent nerve fibers of the sural nerve was recorded from single ascending axons below the site of spinal cord transection. Diazepam, 20 micrograms i.t., reduced activity evoked by afferent A delta and C fiber stimulation and by stimulation of afferent A beta fibers. The depressant effect caused by diazepam, 2 mg/kg i.v., on C fiber-evoked ascending activity was reduced by the i.t. injection of the benzodiazepine antagonist, Ro 15-1788 (40 micrograms), an imidazodiazepine. It is concluded that the depression by diazepam of C fiber-evoked ascending activity contributes to pain relief caused by the drug.
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PMID:Depression of nociceptive sensory activity in the rat spinal cord due to the intrathecal administration of drugs: effect of diazepam. 609 60

Neurotransmitters and neuromodulators involved in the function of vestibular nuclei were reviewed with special reference to drugs used for treatment of motion sickness and vertigo. Biochemical, histochemical and electrophysiological studies have demonstrated that acetylcholine is a transmitter candidate from the afferent vestibular nerve to the lateral vestibular nucleus (LVN), because acetylcholine satisfies most criteria for a chemical transmitter in the central nervous system. It is unlikely, however, that monoamines such as noradrenaline, dopamine and serotonin are transmitters in the vestibular neurons, since cell bodies and nerve terminals containing the monoamines have not been detected yet in the vestibular nuclei. Although histamine and H1-receptor blockers inhibit neuron activities in the vestibular nuclei, it is unclear at present whether histaminergic system is directly related to the function of vestibular neurons. It has been established that GABA is an inhibitory transmitter from the cerebellar Purkinje cells to the LVN neurons. Diazepam is considered to enhance the GABA effect on the LVN, thereby modifying the vestibular neuronal firing. Enkephalin-containing cell bodies and nerve terminals are found in the medial vestibular nucleus, and a few substance P-containing neurons have been observed in the vestibular nuclei. However, the functional role of these peptides on the vestibular system remains to be determined. Unlike histamine H1-receptor blockers, vasodilators such as cinnarizine, ifenprodil and adenosine triphosphate, which are effective in treatment of vertigo, produce an enhancement of responsiveness of neuron activities in the vestibular nuclei, probably as a result of an increase in blood flow in the brain.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Experimental vestibular pharmacology: a minireview with special reference to neuroactive substances and antivertigo drugs. 639 58

Injection of substance P (SP) in a rat hindpaw induced extravasation of 125I-labelled albumin in both hindpaws and salivation. Intravenous injection of SP dose-dependently increased vascular permeability. This latter effect was increased in rat paws by captopril, an inhibitor of angiotensin-converting enzyme (ACE), administered locally in combination with diprotin A, an inhibitor of an dipeptidyl(amino)peptidase IV (DAP IV) or phosphoramidon, an inhibitor of neutral endopeptidase (NEP). The increase in permeability induced by SP was inhibited by RP 67580, a NK-1-receptor antagonist. Intravenous injection of capsaicin induced labelled albumin extravasation in rat paws. This effect was increased by combination of captopril with diprotin A or phosphoramidon, but not by captopril associated with amastatin, an inhibitor of aminopeptidase M (AmM). It was suppressed by RP 67580. Injection of collagenase in rat paws triggered a swelling and a local plasma exudation. These responses were reduced by RP 67580 but not by RP 68651, its inactive enantiomer. They were increased by combination of captopril with diprotin A or phosphoramidon in normal rats. The potentiating effects of captopril and diprotin A were suppressed by RP 67580 in normal rats but did not develop in kininogen-deficient rats. The oedema induced by collagenase was also increased by lisinopril, another ACE inhibitor, administered locally in combination with apstatin, an inhibitor of aminopeptidase P (AmP). In rats pretreated by methysergide, collagenase-induced oedema was reduced and can be increased by captopril, by lisinopril, administered alone or by lisinopril associated with apstatin. It is concluded that SP is mainly inactivated in rat paws by ACE, DAP IV and NEP. In collagenase-induced oedema, a low amount of SP would be released from afferent nerve terminals by bradykinin formed in low amounts. Bradykinin is inactivated in rat paws by ACE and AmP. In collagenase-oedema, the pro-inflammatory effects of bradykinin are concealed by the effects of the other mediators.
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PMID:Influence of several peptidase inhibitors on the pro-inflammatory effects of substance P, capsaicin and collagenase. 893 67

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