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)

Angiotensin II type 1a (AT1a), vasopressin V2, and neurokinin 1 (NK1) receptors are seven-transmembrane receptors (7TMRs) that bind and co-internalize with the multifunctional adaptor protein, beta-arrestin. These receptors also lead to robust and persistent activation of extracellular-signal regulated kinase 1/2 (ERK1/2) localized on endosomes. Recently, the co-trafficking of receptor-beta-arrestin complexes to endosomes was demonstrated to require stable beta-arrestin ubiquitination (Shenoy, S. K., and Lefkowitz, R. J. (2003) J. Biol. Chem. 278, 14498-14506). We now report that lysines at positions 11 and 12 in beta-arrestin2 are specific and required sites for its AngII-mediated sustained ubiquitination. Thus, upon AngII stimulation the mutant beta-arrestin2(K11,12R) is only transiently ubiquitinated, does not form stable endocytic complexes with the AT1aR, and is impaired in scaffolding-activated ERK1/2. Fusion of a ubiquitin moiety in-frame to beta-arrestin2(K11,12R) restores AngII-mediated trafficking and signaling. Wild type beta-arrestin2 and beta-arrestin2(K11R,K12R)-Ub, but not beta-arrestin2(K11R,K12R), prevent nuclear translocation of pERK. These findings imply that sustained beta-arrestin ubiquitination not only directs co-trafficking of receptor-beta-arrestin complexes but also orchestrates the targeting of "7TMR signalosomes" to microcompartments within the cell. Surprisingly, binding of beta-arrestin2(K11R,K12R) to V2R and NK1R is indistinguishable from that of wild type beta-arrestin2. Moreover, ubiquitination patterns and ERK scaffolding of beta-arrestin2(K11,12R) are unimpaired with respect to V2R stimulation. In contrast, a quintuple lysine mutant (beta-arrestin2(K18R,K107R,K108R,K207R,K296R)) is impaired in endosomal trafficking in response to V2R but not AT1aR stimulation. Our findings delineate a novel regulatory mechanism for 7TMR signaling, dictated by the ubiquitination of beta-arrestin on specific lysines that become accessible for modification due to the specific receptor-bound conformational states of beta-arrestin2.
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PMID:Receptor-specific ubiquitination of beta-arrestin directs assembly and targeting of seven-transmembrane receptor signalosomes. 1569 45

Behavioral studies have demonstrated that chronic food restriction augments the rewarding and motor-activating effects of centrally injected psychostimulants and direct dopamine (DA) receptor agonists. Recently, it has been shown that intracerebroventricular (i.c.v.) injection of the D-1 DA receptor agonist, SKF-82958, produces an enhanced locomotor-activating effect as well as increased activation of striatal ERK 1/2 MAP kinase, CaM kinase II, CREB, and c-fos in food-restricted (FR) relative to ad libitum fed (AL) rats. Striatal neurons that express the D-1 DA receptor coexpress dynorphin and substance P, and CREB is known to couple D-1 DA receptor stimulation to preprodynorphin (ppD) gene expression. The purpose of the present study was to examine possible genomic consequences of FR using real-time quantitative RT-PCR to measure striatal neuropeptide gene expression 3 h after i.c.v. injection of SKF-82958 (20 microg). Results indicate that, in nucleus accumbens (NAc), basal levels of ppD and preprotachykinin (ppT) mRNA are lower in FR than AL rats. This may reflect a decrease in tonic DA transmission during FR which precedes the compensatory upregulation of postsynaptic D-1 DA receptor-mediated cell signaling. In response to SKF-82958 challenge, however, FR subjects displayed greater levels of ppD and ppT mRNA in NAc than did AL subjects. A similar trend was seen in caudate-putamen (CPu). SKF-82958 also increased preproenkephalin (ppE) mRNA in Nac, but not CPu, with no difference between feeding groups. The present findings regarding ppD and ppT are consistent with prior findings of increased behavioral and cellular responses to acute D-1 DA agonist challenge in FR rats. The functional consequences of increased neuropeptide gene expression in response to acute drug challenge remain to be investigated but may include modulation of behavioral effects that emerge with repeated drug exposure, including sensitization, tolerance, and addiction.
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PMID:Comparison of basal and D-1 dopamine receptor agonist-stimulated neuropeptide gene expression in caudate-putamen and nucleus accumbens of ad libitum fed and food-restricted rats. 1625 73

Fibromyalgia (FMS) is a debilitating disorder characterized by chronic diffuse muscle pain, fatigue, sleep disturbance, depression and skin sensitivity. There are no genetic or biochemical markers and patients often present with other comorbid diseases, such as migraines, interstitial cystitis and irritable bowel syndrome. Diagnosis includes the presence of 11/18 trigger points, but many patients with early symptoms might not fit this definition. Pathogenesis is still unknown, but there has been evidence of increased corticotropin-releasing hormone (CRH) and substance P (SP) in the CSF of FMS patients, as well as increased SP, IL-6 and IL-8 in their serum. Increased numbers of activated mast cells were also noted in skin biopsies. The hypothesis is put forward that FMS is a neuro-immunoendocrine disorder where increased release of CRH and SP from neurons in specific muscle sites triggers local mast cells to release proinflammatory and neurosensitizing molecules. There is no curative treatment although low doses of tricyclic antidepressants and the serotonin-3 receptor antagonist tropisetron, are helpful. Recent nutraceutical formulations containing the natural anti-inflammatory and mast cell inhibitory flavonoid quercetin hold promise since they can be used together with other treatment modalities.
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PMID:Fibromyalgia--new concepts of pathogenesis and treatment. 1656 42

Airway mucus hypersecretion is now recognized as a key pathophysiological feature in many patients with asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis. Consequently, it is important to develop drugs that inhibit mucus hypersecretion in these susceptible patients. Conventional therapies, including anticholinergics, ss2-adrenoceptor agonists, corticosteroids, mucolytics and macrolide antibiotics, have variable efficacy in inhibiting airway mucus hypersecretion, and are less effective in COPD than in asthma. Novel pharmacotherapeutic targets are being investigated, including inhibitors of nerve activity (e.g. large conductance calcium-activated potassium, BKCa, channel activators), tachykinin receptor antagonists, epoxygenase inducers (e.g. benzafibrate), inhibitors of mucin exocytosis (e.g. anti-myristoylated alanine-rich C kinase substrate (MARCKS), peptide and Munc-18B blockers), inhibitors of mucin synthesis and goblet cell hyperplasia (e.g. epidermal growth factor (EGF), receptor tyrosine kinase inhibitors, p38 mitogen-activated protein (MAP), kinase inhibitors, MAP kinase kinase/extracellular signal-regulated kinase (MEK/ERK), inhibitors, human calcium-activated chloride (hCACL2), channel blockers and retinoic acid receptor-a antagonists), inducers of goblet cell apoptosis (e.g. Bax inducers or Bcl-2 inhibitors), and purinoceptor P(2Y2) antagonists to inhibit mucin secretion or P(2Y2) agonists to hydrate secretions. However, real and theoretical differences delineate the mucus hypersecretory phenotype in asthma from that in COPD. More information is required on these differences to identify specific therapeutic targets which, in turn, should lead to rational design of anti-hypersecretory drugs for treatment of airway mucus hypersecretion in asthma and COPD.
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PMID:Treatment of airway mucus hypersecretion. 1658 97

Capsaicin-induced inactivation of sensory neurons has been reported to enhance metastasis of a murine breast cancer cell line, specifically enhancing myocardial metastases. Here we characterized changes in gene expression patterns in primary tumors which developed in capsaicin-treated vs. control mice. We identified a small cohort of genes (17) which all showed significant decreases in expression levels. All of the identified genes have been linked to cell growth, differentiation, and/or cancer progression. Three representative genes, Caspase-7 (an executor of apoptosis), ADAM-10 (A Disintegrin and Metalloprotease), and Elk-3 (a transcriptional repressor of the ternary factor subfamily of the Ets factors) were further investigated. All three showed dramatic downregulation at the protein level in primary tumors from capsaicin-treated animals compared with control (vehicle-treated) animals, and their expression was also lost in cell culture. Elk-3 and Caspase-7 were not expressed in vitro in cultured cell lines, suggesting that their expression was induced by the tumor microenvironment. Loss of Caspase-7 expression can be expected to result in loss of function of apoptotic pathways. At first glance, loss of ADAM-10 expression would be expected to result in decreased invasive capability, due to loss of matrix metalloprotease activity. However, just the opposite appears to be true. We found that ADAM-10 actually hydrolyzes Substance P. Specifically ADAM-10 produces the same growth-inhibitory products from Substance P (i.e., SP (1-7)) that Neprilysin does, so that loss of ADAM-10 expression actually results in loss of production of growth inhibitory peptides from Substance P. Similarly, ADAM-10 also efficiently hydrolyzes Calcitonin Gene-Related Peptide, which may act in concert with Substance P. Finally, overactivity of Ets transcriptional suppressor functions has been linked to inhibition of tumorigenesis (e.g., Erf and Mef), and in addition loss of Elk-3 expression might also be be linked to tumorigenesis via loss of its putative anti-inflammatory activities. There is anecdotal evidence in the literature to indicate that the rest of the down-regulated genes may also contribute to development of a more aggressive phenotype in this breast cancer model.
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PMID:Capsaicin-induced inactivation of sensory neurons promotes a more aggressive gene expression phenotype in breast cancer cells. 1658 63

Primary sensory neurons respond to a vigorous excitation via the capsaicin receptor/TRPV1 cation channel by a phosphorylation of the Jak/STAT pathway as measured by phospho-STAT3, and of the Ras/Raf-MAPK pathway as measured by phospho-MAPK/ERK1/2. In the present investigation a possible involvement of NK1 receptors in the capsaicin-induced activation of these signal transduction pathways was investigated by protein extraction and Western immunoblotting. Phospho-MAPK/ERK1/2 and phospho-STAT3 were determined in the dorsal root ganglia (DRG) and in the sciatic nerve of rats at 3 and 6 h following a systemic capsaicin treatment without or with the pretreatment of the selective NK1 receptor antagonist SR140333 (1 mg/kg s.c.; 3 h before capsaicin). Capsaicin evoked a threefold increase in phospho-ERK in the sciatic nerve and a two- to threefold increase in the DRG at 3 h and 6 h after the treatment. SR140333 markedly attenuated the capsaicin-induced increase in phosphorylated ERK. In the sciatic nerve the difference was significant at each individual time point (3 and 6 h, p < 0.001). In the DRG the difference was significant when the data at 3 h and 6 h were combined (p < 0.05), but not when individual time points were considered. Capsaicin evoked a four- to fivefold increase in phospho-STAT3 in the sciatic nerve and a twofold increase in the DRG at 3 and 6 h after the treatment. SR140333 less markedly attenuated the capsaicin-induced increase in phosphorylated STAT3: whereas in the sciatic nerve the difference was significant when the data at 3 h and 6 h were combined (p < 0.05), no such treatment effect of SR140333 was observed in the DRG. The expression of TRPV1 mRNA, a specific marker of capsaicin-sensitive small sensory neurons, was investigated by RT-PCR 4 days after the capsaicin treatment. Treatment of rats with SR140333 had no influence on the long-term downregulation of TRPV1 mRNA by capsaicin. Based on the present results and previous findings it can be postulated that the capsaicin-induced ERK phosphorylation in sensory neurons is not a direct effect by capsaicin, but that rather substance P release from the stimulated sensory neurons with an NK1-mediated nerve growth factor (NGF) production is involved.
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PMID:The NK1 receptor antagonist SR140333 inhibits capsaicin-induced ERK phosphorylation in sensory neurons. 1678 6

Substance P (SP), a neurotransmitter, may play an important role in neurogenic inflammation. Ginseng has been used extensively in traditional medicine; however, few studies were focused on their anti-allergic effect. Therefore, the effect and mechanism of ginsenoside Rb1 on the SP enhancement of allergic mediators were explored. In this study, SP and dinitrophenyl-bovine serum albumin (DNP-BSA) were used to activate rat basophilic leukemia (RBL)-2H3 cells. The cultured supernatants were assayed for histamine, leukotriene C(4)(LTC(4)) and interleulin-4 (IL-4) production. The mitogen-activated protein kinases (MAPKs) signaling pathway was determined by Western blotting analysis. We found that IgE/DNP-BSA, SP, ginsenoside Rb1, or MAPK specific inhibitors had no effect on cell viability and cytotoxicity. SP (30 microM) alone, did not induce histamine and LTC(4) release, but it enhanced allergen-induced histamine and LTC(4) release. In addition, SP significantly induced and enhanced allergen-activated IL-4. Ginsenoside Rb1 dose-dependently inhibited these effects. SP enhanced the allergen-activated ERK pathway in RBL-2H3 cells, and Rb1 effectively inhibited the ERK pathway activation. Although MAPK specific inhibitors suppressed LTC(4) and IL-4, only U0126 inhibited the SP enhanced histamine release. These results demonstrate that Rb1 dose-dependently inhibited SP enhanced allergen-induced mediator release and its mechanism was through the inhibition of the ERK pathway.
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PMID:Enhancement of the release of inflammatory mediators by substance P in rat basophilic leukemia RBL-2H3 cells. 1684 22

Substance P (SP) selectively activates mast cells that reside in connective tissues. We studied the reactions of bone marrow-derived mast cells (BMMC) of three mouse strains, cultured with or without fibroblasts. BMMC co-cultured with fibroblasts, but not those cultured alone, increased intracellular Ca(2+), released LTB(4) and histamine in response to SP. PD098059 significantly inhibited the release of LTB(4), but not histamine in all strains. SB203580 failed to reduce or slightly impaired the release of LTB(4). These results suggest that mast cells undergo maturation under the influence of fibroblasts, acquiring the responsiveness to SP with Ca(2+) signals and predominantly ERK-MAP kinase.
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PMID:Bone marrow derived mast cell acquire responsiveness to substance P with Ca(2+) signals and release of leukotriene B(4) via mitogen-activated protein kinase. 1695 5

In this study, we have investigated the effects of artemin (ARTN), one of the glial cell line-derived neurotrophic factor (GDNF) family of neurotrophic factors, on C-fibres following nerve injury in the adult rat. GDNF family receptor alpha (GFRalpha) 3, the ligand binding domain of the ARTN receptor, is expressed in 34% of dorsal root ganglion (DRG) cells, predominantly in the peptidergic population of C-fibres and in a proportion of the isolectin B4 (IB4)-binding population. Interestingly, only 30% of GFRalpha3-expressing DRG cells co-expressed RET (the signal transducing domain). In agreement with previous studies, treatment with ARTN prevented many of the nerve injury-induced changes in the histochemistry of both the peptidergic and the IB4-binding populations of small, but not large, diameter DRG cells. In addition, ARTN treatment maintained C-fibre conduction velocity, and C-fibre evoked substance P release within the dorsal horn following nerve injury. ARTN was also protective following capsaicin treatment, which produces selective C-fibre injury. Given the potent neurotrophic actions of ARTN on C-fibres, it may therefore provide potential for the treatment of nerve injury, particularly in the maintenance of small fibre function.
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PMID:Artemin has potent neurotrophic actions on injured C-fibres. 1711 42

Often considered an aggravating but otherwise benign component of chronic obstructive pulmonary disease (COPD), airway mucus hypersecretion is now recognised as a potential risk factor for an accelerated loss of lung function in COPD and is a key pathophysiological feature in many patients, particularly those prone to respiratory tract infection. Consequently, it is important to develop drugs that inhibit mucus hypersecretion in these susceptible patients. Conventional therapy including anticholinergics, beta2-adrenoceoptor agonists, alone or in combination with corticosteroids, mucolytics and macrolide antibiotics are not entirely or consistently effective in inhibiting airway mucus hypersecretion in COPD. Novel pharmacotherapeutic targets are being investigated, including inhibitors of nerve activity (e.g., BK(Ca) channel activators), tachykinin receptor antagonists, epoxygenase inducers (e.g., benzafibrate), inhibitors of mucin exocytosis (e.g., anti-MARCKS peptide and Munc-18B blockers), inhibitors of mucin synthesis and goblet cell hyperplasia (e.g., EGF receptor tyrosine kinase inhibitors, p38 MAP kinase inhibitors, MEK/ERK inhibitors, hCACL2 blockers and retinoic acid receptor-alpha antagonists), inducers of goblet cell apoptosis (e.g., Bax inducers or Bcl-2 inhibitors), and purinoceptor P(2Y2) antagonists to inhibit mucin secretion or P(2Y2) agonists to hydrate secretions. However, real and theoretical differences delineate the mucus hypersecretory phenotype in COPD from that in other hypersecretory diseases of the airways. More information is required on these differences to identify therapeutic targets pertinent to COPD which, in turn, should lead to rational design of anti-hypersecretory drugs for specific treatment of airway mucus hypersecretion in COPD.
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PMID:The role of airway secretions in COPD: pathophysiology, epidemiology and pharmacotherapeutic options. 1714 99


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