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D. G. Lambert - One of the best experts on this subject based on the ideXlab platform.
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Pharmacological profile of the cyclic nociceptin/orphanin FQ analogues c[Cys^10,14]N/OFQ(1–14)NH_2 and c[Nphe^1,Cys^10,14]N/OFQ(1–14)NH_2
Naunyn-Schmiedeberg's Archives of Pharmacology, 2003Co-Authors: M. Kitayama, T. A. Barnes, G. Carra, J. Mcdonald, G. Calo, R. Guerrini, D. J. Rowbotham, G. Smith, D. G. LambertAbstract:In this study we describe the activity of two cyclic nociceptin/orphanin FQ (N/OFQ) peptides; c[Cys^10,14]N/OFQ(1–14)NH_2 (c[Cys^10,14]) and its [Nphe^1] derivative c[Nphe^1,Cys^10,14]N/OFQ(1–14)NH_2 (c[Nphe^1,Cys^10,14]) in native rat and mouse and recombinant human N/OFQ receptors (NOP). Cyclisation may protect the peptide from metabolic degradation. In competition binding studies of rat, mouse and human NOP the following rank order pK_i was obtained: N/OFQ(1–13)NH_2(reference agonist)>N/OFQ=c[Cys^10,14]>>c[Nphe^1Cys^10,14]. In GTPγ^35S studies of Chinese hamster ovary cells expressing human NOP (CHO_hNOP) c[Cys^10,14] (pEC_50 8.29) and N/OFQ(1–13)NH_2 (pEC_50 8.57) were full agonists whilst c[Nphe^1Cys^10,14] alone was inactive. Following 30 min pre-incubation c[Nphe^1Cys^10,14] competitively antagonised the effects of N/OFQ(1–13)NH_2 with a pA_2 and slope factor of 6.92 and 1.01 respectively. In cAMP assays c[Cys^10,14] (pEC_50 9.29, E_max 102% inhibition of the forskolin stimulated response), N/OFQ(1–13)NH_2 (pEC_50 10.16, E_max 103% inhibition) and c[Nphe^1Cys^10,14] (~80% inhibition at 10 μM) displayed agonist activity. In the mouse vas deferens c[Cys^10,14] (pEC_50 6.82, E_max 89% inhibition of electrically evoked contractions) and N/OFQ(1–13)NH_2 (pEC_50 7.47, E_max 93% inhibition) were full agonists whilst c[Nphe^1Cys^10,14] alone was inactive. c[Nphe^1Cys^10,14] (10 μM) competitively antagonised the effects of N/OFQ(1–13)NH_2 with a pK_B of 5.66. In a crude attempt to assess metabolic stability, c[Cys^10,14] was incubated with rat brain membranes and then the supernatant assayed for remaining peptide. Following 60 min incubation 64% of the 1 nM added peptide was metabolised (compared with 54% for N/OFQ-NH_2). In summary, we report that c[Cys^10,14] is a full agonist with a small reduction in potency but no improvement in stability whilst c[Nphe^1Cys^10,14] displays tissue (antagonist in the vas deferens) and assay (antagonist in the GTPγ^35S assay and agonist in cAMP assay) dependent activity.
Giuseppe Cirino - One of the best experts on this subject based on the ideXlab platform.
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L-Cys/CSE/H2S pathway modulates mouse uterus motility and sildenafil effect
Pharmacological Research, 2016Co-Authors: Emma Mitidieri, Erminia Donnarumma, Roberta D'emmanuele Di Villa Bianca, Teresa Tramontano, Vincenzo Brancaleone, Giuseppe Cirino, Raffaella SorrentinoAbstract:Sildenafil, a selective phosphodiesterase type 5 (PDE5) inhibitor, commonly used in the oral treatment for erectile dysfunction, relaxes smooth muscle of human bladder through the activation of hydrogen sulfide (H2S) signaling. H2S is an endogenous gaseous transmitter with myorelaxant properties predominantly formed from L-cysteine (L-Cys) by cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE). Sildenafil also relaxes rat and human myometrium during preterm labor but the underlying mechanism is still unclear. In the present study we investigated the possible involvement of H2S as a mediator of sildenafil-induced effect in uterine mouse contractility. We firstly demonstrated that both enzymes, CBS and CSE were expressed, and able to convert L-Cys into H2S in mouse uterus. Thereafter, sildenafil significantly increased H2S production in mouse uterus and this effect was abrogated by CBS or CSE inhibition. In parallel, L-Cys, sodium hydrogen sulfide or sildenafil but not D-Cys reduced spontaneous uterus contractility in a functional study. The blockage of CBS and CSE reduced this latter effect even if a major role for CSE than CBS was observed. This data was strongly confirmed by using CSE−/−mice. Indeed, the increase in H2S production mediated by L-Cys or by sildenafil was not found in CSE−/−mice. Besides, the effect of H2S or sildenafil on spontaneous contractility was reduced in CSE−/−mice. A decisive proof for the involvement of H2S signaling in sildenafil effect in mice uterus was given by the measurement of cGMP. Sildenafil increased cGMP level that was significantly reduced by CSE inhibition. In conclusion, L-Cys/CSE/H2S signaling modulates the mouse uterus motility and the sildenafil effect. Therefore the study may open different therapeutical approaches for the management of the uterus abnormal contractility disorders.
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hydrogen sulfide as a mediator of human corpus cavernosum smooth muscle relaxation
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Roberta Demmanuele Di Villa Bianca, Raffaele De Palma, Raffaella Sorrentino, Ferdinando Fusco, Ciro Imbimbo, Pasquale Maffia, Louis J Ignarro, Vincenzo Mirone, Giuseppe CirinoAbstract:Hydrogen sulfide (H2S) is synthesized by 2 enzymes, cystathionine β-synthase (CBS) and cystathionine γ-lyase (CSE). l-Cysteine (l-Cys) acts as a natural substrate for the synthesis of H2S. Human penile tissue possesses both CBS and CSE, and tissue homogenates efficiently convert l-Cys to H2S. CBS and CSE are localized in the muscular trabeculae and the smooth-muscle component of the penile artery, whereas CSE but not CBS is also expressed in peripheral nerves. Exogenous H2S [sodium hydrogen sulfide (NaHS)] or l-Cys causes a concentration-dependent relaxation of strips of human corpus cavernosum. l-Cys relaxation is inhibited by the CBS inhibitor, aminoxyacetic acid (AOAA). Electrical field stimulation of human penile tissue, under resting conditions, causes an increase in tension that is significantly potentiated by either propargylglycine (PAG; CSE inhibitor) or AOAA. In rats, NaHS and l-Cys promote penile erection, and the response to l-Cys is blocked by PAG. Our data demonstrate that the l-Cys/H2S pathway mediates human corpus cavernosum smooth-muscle relaxation.
Michael S Brown - One of the best experts on this subject based on the ideXlab platform.
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Geranylgeranylated Rab proteins terminating in Cys-Ala-Cys, but not Cys-Cys, are carboxyl-methylated by bovine brain membranes in vitro
Proceedings of the National Academy of Sciences of the United States of America, 1994Co-Authors: Tor E Smeland, Miguel C. Seabra, Joseph L Goldstein, Michael S BrownAbstract:Abstract Geranylgeranylated Rab proteins usually terminate in either Cys-Cys or Cys-Xaa-Cys, where Xaa is Ala, Ser, or Gly. In both classes of proteins, the two cysteines are geranylgeranylated, but only the Cys-Xaa-Cys class has been shown to be carboxyl-methylated on the terminal cysteine in vivo. In the current study, we used recombinant Rab geranylgeranyltransferase and a Rab escort protein (REP-1) to attach geranylgeranyl residues to the two cysteines at the carboxyl terminus of Rab3A (Cys-Ala-Cys) and Rab1A (Cys-Cys). The geranylgeranylated proteins were then incubated with bovine cerebellar membranes that contain an enzyme that transfers [3H]methyl from S-[methyl-3H]adenosyl-L-methionine to geranylgeranylated cysteine. The enzyme transferred [3H]methyl to geranylgeranylated Rab3A but not to geranylgeranylated Rab1A. Replacement of the Cys-Ala-Cys terminus of Rab3A with Cys-Cys abolished methylation, and the opposite result was obtained when the Cys-Cys of Rab1A was replaced with Cys-Ala-Cys. When the Cys-Cys terminus of Rab1A was changed to Ser-Cys, methylation was restored. These studies suggest that the carboxyl-terminal cysteine of Rab proteins terminating in Cys-Xaa-Cys but not Cys-Cys is methylated and that the resistance of Cys-Cys proteins to methylation is attributable to the vicinal geranylgeranylated cysteines.
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rab geranylgeranyl transferase a multisubunit enzyme that prenylates gtp binding proteins terminating in cys x cys or cys cys
Journal of Biological Chemistry, 1992Co-Authors: Miguel C. Seabra, Joseph L Goldstein, Thomas C Sudhof, Michael S BrownAbstract:Rab proteins are membrane-bound prenylated GTP-binding proteins required for the targeted movement of membrane vesicles from one organelle to another. In the current paper we have characterized and purified an enzyme that attaches geranylgeranyl residues to Rab proteins that bear the COOH-terminal sequence Cys-X-Cys (such as Rab3A) and Cys-Cys (such as Rab1A). This enzyme is designated Rab geranylgeranyl transferase (Rab GG transferase). At high salt concentrations, Rab GG transferase from rat brain cytosol separates into two components, designated A and B, both of which are required for activity. We purified Component B to apparent homogeneity and found that it contains two peptides of 60 and 38 kDa. The purified Rab GG transferase did not attach geranylgeranyl to p21H-ras-CVLL, which is prenylated by a GG transferase of the CAAX type that resembles the CAAX farnesyltransferase. Rab GG transferase was strongly inhibited by Zn2+, a cation that is absolutely required by farnesyltransferase. The Rab GG transferase was also inhibited by NaCl concentrations in excess of 100 mM. Together with previous data, the current findings indicate that mammalian cells possess at least three protein prenyltransferases (CAAX farnesyltransferase, CAAX GG transferase, and Rab GG transferase) that are specific for different classes of low molecular weight GTP-binding proteins and other proteins.
M. Kitayama - One of the best experts on this subject based on the ideXlab platform.
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Pharmacological profile of the cyclic nociceptin/orphanin FQ analogues c[Cys^10,14]N/OFQ(1–14)NH_2 and c[Nphe^1,Cys^10,14]N/OFQ(1–14)NH_2
Naunyn-Schmiedeberg's Archives of Pharmacology, 2003Co-Authors: M. Kitayama, T. A. Barnes, G. Carra, J. Mcdonald, G. Calo, R. Guerrini, D. J. Rowbotham, G. Smith, D. G. LambertAbstract:In this study we describe the activity of two cyclic nociceptin/orphanin FQ (N/OFQ) peptides; c[Cys^10,14]N/OFQ(1–14)NH_2 (c[Cys^10,14]) and its [Nphe^1] derivative c[Nphe^1,Cys^10,14]N/OFQ(1–14)NH_2 (c[Nphe^1,Cys^10,14]) in native rat and mouse and recombinant human N/OFQ receptors (NOP). Cyclisation may protect the peptide from metabolic degradation. In competition binding studies of rat, mouse and human NOP the following rank order pK_i was obtained: N/OFQ(1–13)NH_2(reference agonist)>N/OFQ=c[Cys^10,14]>>c[Nphe^1Cys^10,14]. In GTPγ^35S studies of Chinese hamster ovary cells expressing human NOP (CHO_hNOP) c[Cys^10,14] (pEC_50 8.29) and N/OFQ(1–13)NH_2 (pEC_50 8.57) were full agonists whilst c[Nphe^1Cys^10,14] alone was inactive. Following 30 min pre-incubation c[Nphe^1Cys^10,14] competitively antagonised the effects of N/OFQ(1–13)NH_2 with a pA_2 and slope factor of 6.92 and 1.01 respectively. In cAMP assays c[Cys^10,14] (pEC_50 9.29, E_max 102% inhibition of the forskolin stimulated response), N/OFQ(1–13)NH_2 (pEC_50 10.16, E_max 103% inhibition) and c[Nphe^1Cys^10,14] (~80% inhibition at 10 μM) displayed agonist activity. In the mouse vas deferens c[Cys^10,14] (pEC_50 6.82, E_max 89% inhibition of electrically evoked contractions) and N/OFQ(1–13)NH_2 (pEC_50 7.47, E_max 93% inhibition) were full agonists whilst c[Nphe^1Cys^10,14] alone was inactive. c[Nphe^1Cys^10,14] (10 μM) competitively antagonised the effects of N/OFQ(1–13)NH_2 with a pK_B of 5.66. In a crude attempt to assess metabolic stability, c[Cys^10,14] was incubated with rat brain membranes and then the supernatant assayed for remaining peptide. Following 60 min incubation 64% of the 1 nM added peptide was metabolised (compared with 54% for N/OFQ-NH_2). In summary, we report that c[Cys^10,14] is a full agonist with a small reduction in potency but no improvement in stability whilst c[Nphe^1Cys^10,14] displays tissue (antagonist in the vas deferens) and assay (antagonist in the GTPγ^35S assay and agonist in cAMP assay) dependent activity.
Jeong Song - One of the best experts on this subject based on the ideXlab platform.
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the behavior of emerging market sovereigns credit default swap premiums and bond yield spreads
International Journal of Finance & Economics, 2010Co-Authors: Michael Adler, Jeong SongAbstract:We test whether credit risk for Emerging Market Sovereigns is priced equally in the credit default swap (CDS) and bond markets. The parity relationship between CDS premiums and bond yield spreads (BYS), that was tested and largely confirmed in the literature, is mostly rejected. Prices below par can result in positive basis, i.e. CDS premiums that are greater than BYS and vice versa. To adjust for the non-par price, we construct the BYS implied by the term structure of CDS premiums for various maturities. We are able to restore the parity relation and confirm the equivalence of credit risk pricing in the CDS and bond markets for many countries that have bonds with non-par prices and time varying credit quality. We detect non-parity even after the adjustment mainly in countries in Latin America, where the bases are larger than the bid-ask spreads in the market. We also find that the repo rates of bonds decrease around episodes of credit quality deterioration, which helps the basis remain positive. Copyright © 2009 John Wiley & Sons, Ltd.
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the behavior of emerging market sovereigns credit default swap premiums and bond yield spreads
International Journal of Finance & Economics, 2010Co-Authors: Michael Adler, Jeong SongAbstract:We test whether credit risk for Emerging Market Sovereigns is priced equally in the credit default swap (CDS) and bond markets. The parity relationship between CDS premiums and bond yield spreads (BYS), that was tested and largely confirmed in the literature, is mostly rejected. Prices below par can result in positive basis, i.e. CDS premiums that are greater than BYS and vice versa. To adjust for the non-par price, we construct the BYS implied by the term structure of CDS premiums for various maturities. We are able to restore the parity relation and confirm the equivalence of credit risk pricing in the CDS and bond markets for many countries that have bonds with non-par prices and time varying credit quality. We detect non-parity even after the adjustment mainly in countries in Latin America, where the bases are larger than the bid-ask spreads in the market. We also find that the repo rates of bonds decrease around episodes of credit quality deterioration, which helps the basis remain positive. Copyright © 2009 John Wiley & Sons, Ltd.
