Dimerization of 8-OH-DPAT increases activity at serotonin 5-HT1A receptors.
[35S]GTPgammaS binding responses can be used to measure differences between the intrinsic activity of ligands at human 5-hydroxytrypamine-(1A) (h 5-HT1A) receptors expressed in recombinant cell lines. The maximal [35S]GTPgammaS binding response to 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was lower than that to 5-HT in a recombinant C6-glial membrane preparation and dependent on the GDP concentration: it was attenuated by about 60% vs 5-HT by increasing the concentration of GDP from 0.3 to 30 and 300 microM. Whereas dimerization of 8-OH-DPAT almost did not affect its potency at h 5-HT1A receptors (pEC50: 7.45 and 7.40 for 8-OH-DPAT and its dimer at 30 microM GDP), it increased efficacy at h 5-HT1A receptors. The maximal response to the 8-OH-DPAT dimer was systematically greater than the response to 8-OH-DPAT and identical to that to 5-HT; moreover in contrast to the 8-OH-DPAT monomer, the maximal response to the dimer was unaffected by increasing the GDP concentration. An enhanced 135S]GTPgammaS binding response (44 to 63% vs 8-OH-DPAT) was also observed in the hippocampus, lateral septum, dorsal raphe and cingulate cortex of guinea-pig brain sections using autoradiography of 5-HT1A receptor-activated G-proteins. Hence, the 8-OH-DPAT dimer shows increased efficacy at 5-HT1A receptors compared to 8-OH-DPAT. The differential regulation of the maximal agonist responses by GDP suggests that the [35S]GTPgammaS binding responses to these two ligands could be mediated by different G-protein subtypes upon activation of the 5-HT1A receptor.
Pauwels
P J
PJ
Centre de Recherche Pierre Fabre, Département de Biologie Cellulaire et Moléculaire, Castres, France. peter.pauwels@pierre-fabre.com
Dupuis
D S
DS
Perez
M
M
Halazy
S
S
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001345:Autoradiography; D019281:Dimerization; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006168:Guinea Pigs; D006367:HeLa Cells; D006801:Humans; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D017371:8-Hydroxy-2-(di-n-propylamino)tetralin