Interaction of 5-HT1B/D ligands with recombinant h 5-HT1A receptors:Intrinsic activity and modulation by G-protein activation state

Many 5-HT_1B/D receptor ligands have affinity for 5-HT_1A receptors. In the present study, the intrinsic activity of a series of 5-HT_1B/D ligands was investigated at human 5-HT_1A (h 5-HT_1A) receptors by measuring G-protein activation in recombinant C6-glial and HeLa membranes, using agonist-stimulated [³⁵S]GTPγS binding. In these two membrane preparations, the density of h 5-HT_1A 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]GTPγS binding responses induced by the 5-HT_1B/D receptor ligands in the HeLa preparation at 30 μM 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 μM 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]GTPγS binding responses induced by 5-HT_1B/D ligands in the C6-glial preparation were either unaffected or significantly enhanced by increasing the GDP concentration from 0.3 to 30 μM and higher concentrations. These features differ from those observed with 5-HT_1A 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-HT_1A and 5-HT_1B/D agonist responses by GDP suggests that different G-protein subtypes are involved upon 5-HT_1A receptor activation by 5-HT_1A and 5-HT_1B/D agonists. Received: 28 October 1997 / Accepted: 14 February 1998