title: Interaction of 5-HT1B/D ligands with recombinant h 5-HT1A receptors: intrinsic activity and modulation by G-protein activation state.
abstract: Many 5-HT1B/D receptor ligands have affinity for 5-HT1A receptors. In the present study, the intrinsic activity of a series of 5-HT1B/D ligands was investigated at human 5-HT1A (h 5-HT1A) receptors by measuring G-protein activation in recombinant C6-glial and HeLa membranes, using agonist-stimulated [35S]GTPgammaS binding. In these two membrane preparations, the density of h 5-HT1A receptors (i.e., 246 to 320 fmol mg(-1) protein) and of their G-proteins, and the receptor: G-protein density ratio (0.08 to 0.18) appeared to be similar. It was found that: (i) the maximal [35S]GTPgammaS binding responses induced by the 5-HT1B/D receptor ligands in the HeLa preparation at 30 microM GDP were comparable to that of the native agonist 5-HT; (ii) as compared to 5-HT (1.00), similar potencies but lower maximal responses were observed in the C6-glial preparation at 0.3 microM GDP for zolmitriptan (0.89), dihydroergotamine (0.81), rizatriptan (0.71), CP122638 (0.69), naratriptan (0.60) and sumatriptan (0.53); and that (iii) maximal [35S]GTPgammaS binding responses induced by 5-HT1B/D ligands in the C6-glial preparation were either unaffected or significantly enhanced by increasing the GDP concentration from 0.3 to 30 microM and higher concentrations. These features differ from those observed with 5-HT1A receptor agonists; the latter display the same rank order of potency and efficacy in both membrane preparations, and increasing the amount of GDP with C6-glial membranes results in an attenuation of both the agonist's maximal effect and the apparent potency of partial agonists. The differential regulation of 5-HT1A and 5-HT1B/D agonist responses by GDP suggests that different G-protein subtypes are involved upon 5-HT1A receptor activation by 5-HT1A and 5-HT1B/D agonists.
authors.affiliation: Centre de Recherche Pierre Fabre, Department of Cellular and Molecular Biology, Castres, France.
authors.forename: P J
authors.initials: PJ
authors.lastname: Pauwels
authors.forename: C
authors.initials: C
authors.lastname: Palmier
authors.forename: D S
authors.initials: DS
authors.lastname: Dupuis
authors.forename: F C
authors.initials: FC
authors.lastname: Colpaert
mesh_terms: D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004087:Dihydroergotamine / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006153:Guanosine Diphosphate / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D008090:Lisuride / Q000494:pharmacology; D009457:Neuroglia / Q000378:metabolism*; D011869:Radioligand Assay; D011985:Receptors, Serotonin / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
chemical_list: D011985:Receptors, Serotonin; D011994:Recombinant Proteins; D017366:Serotonin Receptor Agonists; D006153:Guanosine Diphosphate; D004087:Dihydroergotamine; D008090:Lisuride; D019204:GTP-Binding Proteins