INT25271
From wiki-pain
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Sentences Mentioned In
Key: | Protein | Mutation | Event | Anatomy | Negation | Speculation | Pain term | Disease term |
In the present study, we have further explored this issue by examining density, mRNA expression and activation of GTP-binding proteins for the cannabinoid CB1 receptor subtype in several brain structures of mice with chronic relapsing experimental allergic encephalomyelitis (CREAE), a chronic model of MS that reproduces many of the pathological hallmarks of the human disease. | |||||||||||||||
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High activities of serum AIP, LAP and gamma-GTP were observed. | |||||||||||||||
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Frequency of the arterial hypertension was the same in both groups, whereas acroparesthesias, Raynaud's syndrome, and increased gamma GTP serum activity were significantly more frequent in workers with neurological disturbances. | |||||||||||||||
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Aluminum fluoride, known to activate GTP binding proteins, also reduced potentials and this was antagonized by morphine. | |||||||||||||||
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Furthermore, expression of epidermal growth factor receptor (EGFR) and its ligands; serine protease inhibitor Kazal type 3 (Spink3) and transforming growth factor alpha (TGF alpha) and activation of K-Ras (GTP-Ras formation), which are frequently observed in human PDA, were indeed observed in parallel with TCs formation. | |||||||||||||||
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The inward current induced by VIP became irreversible after the intracellular administration of GTP gamma S, a hydrolysis-resistant analog of GTP which can cause a prolonged activation of G-proteins. | |||||||||||||||
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Further, (+)-5a potently stimulated GTP gamma S binding to NOP membranes (EC50 = 65 nM) and inhibited forskolin-mediated cAMP accumulation in NOP-expressing cells (EC50 = 9.1 nM) with a potency comparable to that of the natural peptide agonist N/OFQ. | |||||||||||||||
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It further appeared that 6-times more h5-HT1D than h5-HT1B binding sites were required to attain a similar, maximal (73%), 5-HT-stimulated [35S]GTP gamma S binding response: Hence, the h5-HT1B receptor in C6-glial cell membranes could be more efficiently coupled, even though some compounds more readily displayed intrinsic activity at h5-HT1D receptor sites [e.g. dihydroergotamine and (2'-methyl-4'-(5-methyl[1,2,4]oxadiazol-3-yl)biphenyl-4-carboxylic acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide (GR127935)]. | |||||||||||||||
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Efficacy differences were apparent for most of the compounds (sumatriptan, zolmitriptan, rizatriptan, N-methyl-3-[pyrrolidin-2(R)-ylmethyl]-1H-indol-5-ylmethyl sulfonamide (CP122638), dihydroergotamine, naratriptan and GR127935) that stimulated [35S]GTP gamma S binding compared to the native agonist 5-HT. | |||||||||||||||
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N/OFQ stimulation increased [35S]GTP gamma S binding to cell membranes and attenuated forskolin-induced cAMP accumulation in a concentration-dependent manner. | |||||||||||||||
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Biochemical, pharmacological and molecular biology studies suggest several molecular mechanisms of the bimodal activity of opioids, including the coupling of opioid receptors to various GTP-binding proteins, the involvement of different subunits of these proteins, and the activation of several intracellular signal transduction pathways. | |||||||||||||||
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Under the conditions of the [35S]GTP gamma S assay, binding of agonists was to a high affinity site, indicating that a high agonist affinity state of the mu-opioid receptor is responsible for the observed stimulation of [35S]GTP gamma S binding. | |||||||||||||||
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The serum LDH, GOT, GPT, ALP and gamma-GTP levels were elevated, and antibodies to Epstein-Barr viral capsid, early, and nuclear antigens were diagnostic of a primary Epstein-Barr virus infection. | |||||||||||||||
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Laboratory data other than leukocytosis and elevated level of gamma-GTP were normal and the results of brain CT scan were within normal limits. | |||||||||||||||
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The net effect of unregulated activation and inactivation is a subtle increase in the duration of association of active Rab7 with target membranes and an increase in the GTP-bound, active fraction (Figs. 3, 4, and 5).
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This finding indicates that accelerated GTP exchange in disease mutants leads to an increase in the active, GTP-bound fraction of Rab7.
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Although a previous report concluded that disease mutants have a GTPase defect (21), we demonstrate that this apparent defect is largely a reflection of increased GTP dissociation. | |||||||||||||||
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We found that the Rab7 compound mutants largely rescued the FRAP defect seen in the Q67L mutant alone, suggesting that the Rab7 disease-causing mutations increase GTP dissociation and lead to GTPase-independent membrane cycling of Rab7 in vivo (Fig. 6C). | |||||||||||||||
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Surprisingly, the cellular phenotype of mutant Rab7 is milder than expected given the prominent, unregulated GTP exchange and marked increase in the active fraction. | |||||||||||||||
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Up to the 25 mg/kg dose level, one DLT (Grade 3 gamma-GTP increase at a dose of 25 mg/kg) was observed. | |||||||||||||||
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General Comments
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