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Titolo:
PHARMACOLOGICAL ANALYSIS OF G-PROTEIN ACTIVATION MEDIATED BY GUINEA-PIG RECOMBINANT 5-HT1B RECEPTORS IN C6-GLIAL CELLS - SIMILARITIES WITH THE HUMAN 5-HT1B RECEPTOR
Autore:
PAUWELS PJ; WURCH T; PALMIER C; COLPAERT FC;
Indirizzi:
CTR RECH PIERRE FABRE,DEPT CELLULAR & MOL BIOL,17 AVE JEAN MOULIN F-81106 CASTRES FRANCE
Titolo Testata:
British Journal of Pharmacology
fascicolo: 1, volume: 123, anno: 1998,
pagine: 51 - 62
SICI:
0007-1188(1998)123:1<51:PAOGAM>2.0.ZU;2-3
Fonte:
ISI
Lingua:
ENG
Soggetto:
5-HYDROXYTRYPTAMINE1B RECEPTOR; 5-HT1D-BETA RECEPTORS; MOLECULAR-CLONING; RAT-BRAIN; 5-HT1D-ALPHA; AUTORECEPTOR; ANTAGONISTS; BINDING; IDENTIFICATION; 5-HT(1B);
Keywords:
GUINEA-PIG RECOMBINANT 5-HT1B RECEPTOR; HUMAN 5-HT1B RECEPTOR; [S-35] GTP-GAMMA-S BINDING RESPONSE; AGONIST/INVERSE AGONIST; RAT C6-GLIAL CELL LINE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
46
Recensione:
Indirizzi per estratti:
Citazione:
P.J. Pauwels et al., "PHARMACOLOGICAL ANALYSIS OF G-PROTEIN ACTIVATION MEDIATED BY GUINEA-PIG RECOMBINANT 5-HT1B RECEPTORS IN C6-GLIAL CELLS - SIMILARITIES WITH THE HUMAN 5-HT1B RECEPTOR", British Journal of Pharmacology, 123(1), 1998, pp. 51-62

Abstract

1 The guinea-pig recombinant 5-hydroxytryptamine(1B), (gp 5-HT1B) receptor stably transfected in rat C6-glial cells was characterized by monitoring G-protein activation in a membrane preparation with agonist-stimulated [S-35]-GTP gamma S binding. The intrinsic activity of 5-HT receptor ligands was compared with that determined previously at the human recombinant 5-HT1B (h 5-HT1B) receptor under similar experimental conditions. 2 Membrane preparations of C6-glial/gp 5-HT1B cells exhibited [H-3]-5-carboxamidotryptamine (5-CT) and [H-3]- N- [4-methoxy-3,4-methylpiperazin-1-yl) phenyl]-3-methyl-4-(4-pyridinyl)benzamide (GR 125743) binding sites with a pK(d) of 9.62 to 9.85 and a B-max,,, between 2.1 to 6.4 fmol mg(-1) protein. The binding affinities of a series of 5-HT receptor ligands determined with [H-3]-5-CT and [H-3]-GR 125743were similar. Ligand affinities were comparable to and correlated (r(2): 0.74, P<0.001) with those determined at the recombinant h 5-HT1B receptor. 3 [S-35]-GTP gamma S binding to membrane preparations of C6-glial/gp 5-HT1B cells was stimulated by the 5-HT receptor agonists thatwere being investigated. The maximal responses of naratriptan, zolmitriptan, sumatriptan, din-2(R)-ylmethyl]-1H-indol-5-ylmethylsulphonamide (CP 122638), rizatriptan and dihydroergotamine were between 0.76 and0.85 compared to 5-HT. The potency of these agonists showed a positive correlation (r(2): 0.72, P=0.015) with their potency at the recombinant h 5-HT1B receptor. 1-naphthylpiperazine, (+/-)-cyanopindolol and (2'-methyl-4'-(5-methyl[1,2,4] oxadiazole-3-yl)biphenyl-4-carboxylic acid [4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]amide (GR 127935) elicited an even smaller response (E-max: 0.32 to 0.63). 4 The ligands l-5-(2'-methyl-4'-(5-methyl-1,2,4-oxadiazole-3-yl) biphenyl-4-carbonyl)-2,3,6,7-tetrahydrospiro [furo[2,3-f]indole-3-spiro-4'-piperidine] (SB224289), methiothepin and ritanserin displayed inhibition of basal [S-35]-GTP gamma S binding at concentrations relevant to their binding affinity for the gp 5-HT1B receptor. Methiothepin and SB224289 behaved as competitive antagonists at gp 5-HT1B receptors; pA(2) values were 9.74 and 8.73, respectively when 5-HT was used as an agonist. These estimates accorded with the potencies measured in antagonism of zolmitriptan-mediated inhibition of forskolin-stimulated cyclic AMP formation. Ketanserin acted as a weak antagonist (pK(B): 5.87) at gp 5-HT1B receptors. 5 In conclusion, the recombinant gp 5-HT1B receptor shares importantpharmacological similarities with the recombinant h 5-HT1B receptor. The finding that negative activity occurs at these receptors further suggests that SB224289, methiothepin and ritanserin are likely to be inverse agonists.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 29/03/20 alle ore 14:46:45