Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Preprodynorphin (PPD) and preproenkephalin (PPE) gene expression in a rat model of orofacial inflammation were examined in order to further characterize the neurochemical mechanisms underlying orofacial inflammation and hyperalgesia. Deep and cutaneous orofacial inflammation was produced by a unilateral injection of complete Freund's adjuvant (CFA) into the rat temporomandibular joint (TMJ) or perioral skin (PO), respectively. RNA blot analysis of the tissues including the spinal trigeminal complex revealed that the PPD mRNA level ipsilateral to TMJ inflammation was increased by 56.5+/-14.7% (n=4) when compared to the Naive group, and was significantly greater than the contralateral PPD mRNA level (p<0.05). The distribution of neurons that exhibited PPD mRNA after inflammation was localized by in situ hybridization (naive approximately 0). In TMJ-inflamed rats (n=6) PPD mRNA-positive neurons were found ipsilaterally in the medial portion of laminae I-II of the upper cervical dorsal horn (4.5+/-0.3), the dorsal portion of the subnucleus caudalis and caudal subnucleus interpolaris (5.2+/-0.3), and the paratrigeminal nucleus (6.4+/-1.2). A very localized induction of PPD mRNA was also identified in a group of neurons in the intermediate portion of the subnucleus caudalis (2.4+/-0.4) in PO-inflamed rats (n=6). The distribution of these PPD mRNA-positive neurons was somatotopically relevant to the site of injury. There were no significant changes in PPE mRNA expression in both TMJ- and PO-inflamed rats. These results indicate that TMJ inflammation resulted in a more intense and widespread increase in PPD mRNA expression when compared to PO inflammation. These changes may contribute to persistent central hyperexcitability and pain associated with temporomandibular disorders.
Brain Res Mol Brain Res 1999 Apr 06
PMID:Orofacial deep and cutaneous tissue inflammation differentially upregulates preprodynorphin mRNA in the trigeminal and paratrigeminal nuclei of the rat. 1010 Dec 36

Neuropeptides FF (NPFF), AF (NPAF), and SF (NPSF) are homologous amidated peptides that were originally identified on the basis of similarity to the molluscan neuropeptide FMRF-amide. They have been hypothesized to have wide-ranging functions in the mammalian central nervous system, including pain modulation, opiate function, cardiovascular regulation, and neuroendocrine function. We have cloned the NPFF gene from human, bovine, rat, and mouse, and show that the precursor mRNA encodes for all three of the biochemically identified peptides (NPFF, NPAF, and NPSF). We demonstrate that NPFF precursor mRNA expression by Northern analysis and map sites of expression by in situ hybridization. We confirm the validity of the in situ hybridization by showing that its distribution in the brain and spinal cord matches the distribution of NPFF and NPSF immunoreactivity. We go on to show that the mRNA levels (as measured by in situ hybridization) in the spinal cord can be up-regulated by a model for inflammatory pain (carrageenan injection), but not by a model for neuropathic pain (lumbar nerve ligation). Our results confirm the evolutionary conservation of NPFF, NPAF, and NPSF neuropeptide expression in mammalian brain. They also provide a context for the interpretation of the pain-sensitizing effects of injections of these peptides that have been previously reported. Our results support a model for the role of these peptides in pain regulation at the level of the spinal cord.
Mol Pharmacol 1999 May
PMID:Gene for pain modulatory neuropeptide NPFF: induction in spinal cord by noxious stimuli. 1022 May 58

Substance P receptor (SPR), which plays a key role in pain transmission, is known to undergo rapid agonist-dependent desensitization and internalization. The present study shows that human SPR undergoes agonist-dependent phosphorylation in intact cells. Immunoprecipitation of SPR from 32Pi-labeled Chinese hamster ovary cells stably expressing human SPR (CHO-hSPR) indicates that substance P (SP) causes a rapid (T1/2 < 1 min), dose-dependent (EC50 = 2 nM), and pronounced (5-fold over basal) phosphorylation of SPR. Because SPR in CHO-hSPR couples to Galphaq, Galphas, and Galphao (), we examined the involvement of various second messenger-activated protein kinases in SPR phosphorylation. Although increases in intracellular cyclic AMP or treatment with the calcium ionophore A23187 do not cause SPR phosphorylation, treatment with the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) causes a 2.5-fold increase in SPR phosphorylation with a T1/2 of <1 min. However, PKC inhibitor GF109203X has no effect on SP-dependent SPR phosphorylation. Furthermore, although SP treatment phosphorylates SPR on both serine and threonine residues equally, PMA treatment phosphorylates the receptor predominantly on serine residues. Two-dimensional phosphopeptide mapping data indicate that SP-dependent and PMA-dependent phosphorylations of SPR have some unique differences. Taken together, these data suggest that although activation of PKC by PMA can lead to SPR phosphorylation, PKC does not mediate SP-dependent phosphorylation of SPR. In conclusion, the present study represents the first demonstration and characterization of agonist-dependent and PMA-mediated phosphorylation of SPR in intact cells.
Mol Pharmacol 1999 May
PMID:Characterization of differences between rapid agonist-dependent phosphorylation and phorbol ester-mediated phosphorylation of human substance P receptor in intact cells. 1022 May 64

Elevated formation of bradykinin (BK) and Lys-BK or kallidin (KD) and their carboxypeptidase metabolites desArg(9)BK and desArg(10)KD is evident at sites of inflammation. Moreover, B2 receptors (B2R), which mediate the action of BK and KD, participates in the acute stage of the inflammatory and pain response, whereas B1 receptors (B1R), through which desArg(9)BK and desArg(10)KD act, partake in the chronic stage. We hypothesized that kinins autoregulate B2R and B1R expression in favor of B1R. Incubation of IMR-90 cells with BK (100 nM) led to a loss (89%) of B2R with a half-life (T(1/2)) of 7.0 min. Concomitantly, BK increased B1R (2- to 3-fold) with a T(1/2) of 120 min. DesArg(10)KD (100 nM) had no effect on B2R but increased B1R (3- to 4-fold) with the same rate as BK. Interleukin-1beta (IL-1beta; 500 pg/ml) also increased B1R (4- to 6-fold). Although both desArg(10)KD and BK increased the level of IL-1beta mRNA, IL-1beta receptor antagonist inhibited the increase in B1R only in response to BK. DesArg(10)KD and BK synergistically increased B1R (9-fold), which was further increased by inclusion of IL-1beta (36-fold). Therefore, kinin metabolism and kinin-stimulated production of cytokines may play a pivotal role in shifting the repertoire of kinin receptor subtypes in favor of B1R during inflammation.
Mol Pharmacol 1999 Aug
PMID:Autoregulation of bradykinin receptors: agonists in the presence of interleukin-1beta shift the repertoire of receptor subtypes from B2 to B1 in human lung fibroblasts. 1041 51

Circulating autoimmune complexes of IgM rheumatoid factors (RF) bound to the Fc portions of normal, polyclonal IgG antibodies are frequently present in humans with rheumatoid arthritis (RA). The sweet tasting methyl ester of L-Asp-L-Phe (aspartame or APM) was found to relieve pain and improve joint mobility in subjects with osteo- and mixed osteo/rheumatoid arthritis [Edmundson, A. B. and Manion, C. V. (1998). Clin. Pharmac. Ther. 63, 580-593]. These clinical observations prompted the testing of the inhibition by APM of the binding interactions of human IgM RFs with IgG Fc regions. The propensity of APM to inhibit IgM RF binding was assessed by competitive enzyme immunoassays with solid-phase human IgG. Ten RA serum samples and three purified monoclonal cryoglobulins, all of which had RF activity, were tested in this system. We found that the presence of APM significantly reduced the binding of IgM RFs. The inhibitory propensity of APM with monoclonal RF cryoglobulins was increased by the addition of CaCl(2) to the binding buffer. Similar inhibition of the binding of RA derived RFs to IgG was observed for Asp-Phe and its amidated derivative, indicating that the methyl ester is not required for APM's interaction with IgM antibodies. A human (Mez) IgM known to bind octameric peptides derived from the Fc portion of a human IgG(1) antibody was tested for binding of dipeptides by the Pepscan method of combinatorial chemistry. The relative binding constants of Asp-Phe and Phe-Asp were ranked among the highest values for 400 possible combinations of the 20 most common amino acids. Possible blocking interactions of APM were explored by computer-assisted docking studies with the model of a complex of an RF Fab with the Fc of a human IgG(4) antibody. Modeling of ternary immune complexes revealed a few key residues, which could act as molecular recognition sites for APM. A structural hypothesis is presented to explain the observed interference with RF reactivity by APM. Extrapolations of the current results suggest that APM may inhibit the binding of IgG in a substantial proportion of IgM RFs. Interference of RF reactivity, especially in RA patients, may alleviate the pain and immobility resulting from chronic inflammation of the joints.
J Mol Recognit
PMID:Interference of rheumatoid factor activity by aspartame, a dipeptide methyl ester. 1077 54

The role of endothelin B (ET(B)) receptors in inflammation and nociception was examined using ET(B) receptor knockout mice. Genotyping studies were used with tissues from ET(B)((+/+)), ET(B)((+/-)), and ET(B)((-/-)) mice to confirm the loss of ET(B) receptors. Algesia induced by phenylbenzoquinone was evident in the (+/+) mice, reduced by approximately 80% in the (+/-) mice, and absent in the (-/-) mice. Phenylbenzoquinone-induced algesia in (+/+) mice was inhibited 74% by the ET(B) receptor-selective antagonist A192621 (25 mg/kg p.o.), but unaffected by the ET(A) receptor-selective antagonist SB 234551 (25 mg/kg p.o.). Noninflammatory pain, induced by hotplate, was equivalent between (+/+) and (-/-) mice. The cutaneous inflammatory response to topical arachidonic acid (AA) also was evaluated. Whereas (+/+) mice had a marked inflammatory response to AA, the (+/-), and (-/-) mice had significantly reduced fluid phase responses (37 and 65% inhibition, respectively). Neutrophil infiltration also was reduced in the (+/-) and (-/-) mice (51 and 65% reduction, respectively). Topical administration of A192621 (500 microg/ear) in (+/+) mice inhibited AA-induced swelling (39%), whereas SB 234551 (500 microg/ear) was without effect. Collectively, these results implicate the ET(B) receptor in mediation of inflammatory pain and cutaneous inflammatory responses in mice.
Mol Pharmacol 1999 Oct
PMID:Endothelin B receptor modulates inflammatory pain and cutaneous inflammation. 1049 65

The neuropeptide calcitonin gene-related peptide (CGRP) expressed by one-third of rat dorsal root ganglion (DRG) neurons mediates pain sensation and vasodilation. The developmental regulation of CGRP is poorly understood, but may involve target-derived factors from skin or viscera. Few embryonic DRG neurons in defined culture express CGRP, indicating inductive signals are required. Follistatin blocked CGRP expression induced by serum or skin-conditioned medium, implicating transforming growth factor beta (TGFbeta) family members. Activin or bone morphogenetic proteins (BMPs) 2, 4, or 6 stimulated CGRP expression in 60% of DRG neurons. Brief BMP4 application supported maximal CGRP induction, suggesting that BMP4 is a "switch" rather than a continuous modulator of neuropeptide phenotype. DRG expressed corresponding receptor subunits and exhibited Smad1 transcription factor nuclear translocation following BMP stimulation. BMP mRNAs were present in embryonic targets innervated by CGRP-expressing neurons. Thus, specific TGFbeta family members are candidate regulators of CGRP expression in sensory neurons.
Mol Cell Neurosci 1999 Dec
PMID:Activin and bone morphogenetic proteins induce calcitonin gene-related peptide in embryonic sensory neurons in vitro. 1065 56

To elucidate the sites of and mechanisms of analgesic effect of centrally injected calcitonin, we examined expression of calcitonin receptor mRNA in the mouse brain by in situ hybridization techniques. Calcitonin receptor mRNA was expressed in various brain regions, including the preoptic area, dorsomedial hypothalamic nucleus, lateral hypothalamic area, periaqueductal gray, dorsal raphe nucleus, locus coeruleus, lateral parabrachial nucleus, gigantocellular reticular nucleus alpha part, lateral paragigantocellular nucleus, raphe magnus nucleus and solitary tract nucleus, which are known to play important roles in pain modulation. In addition, a double in situ hybridization technique demonstrated the intense expression of calcitonin receptor mRNA on serotonergic neurons in some raphe nuclei and the lateral paragigantocellular nucleus, suggesting the involvement of central serotonergic pathways in analgesic effect of calcitonin.
Brain Res Mol Brain Res 2000 Mar 10
PMID:Localization of calcitonin receptor mRNA in the mouse brain: coexistence with serotonin transporter mRNA. 1071 19

Circulating autoimmune complexes of IgM rheumatoid factors (RF) bound to the Fc portions of normal, polyclonal IgG antibodies are frequently present in humans with rheumatoid arthritis (RA). The sweet tasting methyl ester of L-Asp-L-Phe (aspartame or APM) was found to relieve pain and improve joint mobility in subjects with osteo- and mixed osteo/rheumatoid arthritis [Edmundson, A. B. and Manion, C. V. (1998). Clin. Pharmac. Ther. 63, 580-593]. These clinical observations prompted the testing of the inhibition by APM of the binding interactions of human IgM RFs with IgG Fc regions. The propensity of APM to inhibit IgM RF binding was assessed by competitive enzyme immunoassays with solid-phase human IgG. Ten RA serum samples and three purified monoclonal cryoglobulins, all of which had RF activity, were tested in this system. We found that the presence of APM significantly reduced the binding of IgM RFs. The inhibitory propensity of APM with monoclonal RF cryoglobulins was increased by the addition of CaCl(2) to the binding buffer. Similar inhibition of the binding of RA derived RFs to IgG was observed for Asp-Phe and its amidated derivative, indicating that the methyl ester is not required for APM's interaction with IgM antibodies. A human (Mez) IgM known to bind octameric peptides derived from the Fc portion of a human IgG(1) antibody was tested for binding of dipeptides by the Pepscan method of combinatorial chemistry. The relative binding constants of Asp-Phe and Phe-Asp were ranked among the highest values for 400 possible combinations of the 20 most common amino acids. Possible blocking interactions of APM were explored by computer-assisted docking studies with the model of a complex of an RF Fab with the Fc of a human IgG(4) antibody. Modeling of ternary immune complexes revealed a few key residues, which could act as molecular recognition sites for APM. A structural hypothesis is presented to explain the observed interference with RF reactivity by APM. Extrapolations of the current results suggest that APM may inhibit the binding of IgG in a substantial proportion of IgM RFs. Interference of RF reactivity, especially in RA patients, may alleviate the pain and immobility resulting from chronic inflammation of the joints.
J Mol Recognit
PMID:Interference of rheumatoid factor activity by aspartame, a dipeptide methyl ester. 1044 Sep 96

The mitochondrial matrix of the yeast Saccharomyces cerevisiae contains two molecular chaperones of the Hsp70 class, Ssc1 and Ssq1. We report that Ssc1 and Ssq1 play sequential roles in the import and maturation of the yeast frataxin homologue (Yfh1). In vitro, radiolabeled Yfh1 was not imported into ssc1-3 mutant mitochondria, remaining in a protease-sensitive precursor form. As reported earlier, the Yfh1 intermediate form was only slowly processed to the mature form in Deltassq1 mitochondria (S. A. B. Knight, N. B. V. Sepuri, D. Pain, and A. Dancis, J. Biol. Chem. 273:18389-18393, 1998). However, the intermediate form in both wild-type and Deltassq1 mitochondria was entirely within the inner membrane, as it was resistant to digestion with protease after disruption of the outer membrane. Therefore, we conclude that Ssc1, which is present in mitochondria in approximately a 1,000-fold excess over Ssq1, is required for Yfh1 import into the matrix, while Ssq1 is necessary for the efficient processing of the intermediate to the mature form in isolated mitochondria. However, the steady-state level of mature Yfh1 in Deltassq1 mitochondria is approximately 75% of that found in wild-type mitochondria, indicating that this retardation in processing does not dramatically affect cellular concentrations. Therefore, Ssq1 likely has roles in addition to facilitating the processing of Yfh1. Twofold overexpression of Ssc1 partially suppresses the cold-sensitive growth phenotype of Deltassq1 cells, as well as the accumulation of mitochondrial iron and the defects in Fe/S enzyme activities normally found in Deltassq1 mitochondria. Deltassq1 mitochondria containing twofold-more Ssc1 efficiently converted the intermediate form of Yfh1 to the mature form. This correlation between the observed processing defect and suppression of in vivo phenotypes suggests that Ssc1 is able to carry out the functions of Ssq1, but only when present in approximately a 2,000-fold excess over normal levels of Ssq1.
Mol Cell Biol 2000 May
PMID:Role of the mitochondrial Hsp70s, Ssc1 and Ssq1, in the maturation of Yfh1. 1077 57


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