Evidence for two conformational states of 5-hydroxytryptamine carrier in rat cortical synaptosomes.
The effects of SABA ((3-beta-(4-azidobenzamidino)ethyl)-5-hydroxyindole), and fluoxetine, on the uptake of 5-hydroxytryptamine (5-HT; serotonin) by cerebral cortical synaptosomes of the rat were studied under normal (147 mM) and small (29 mM) concentrations of sodium. In the dark, both compounds competitively inhibited the uptake of 5-HT. However, in the presence of a small concentration of sodium (29 mM), the Ki(nM) for SABA decreased from 128 +/- 7 (n = 3) to 93 +/- 7 (n = 3) (P less than 0.05), whereas the Ki for fluoxetine increased from 30 +/- 2 (n = 3) to 59 +/- 6 (n = 3) (P less than 0.05). The maximum irreversible photoinactivation of the uptake of 5-HT by 1 microM SABA was increased by about 20% when the concentration of sodium ions [( Na+]) was decreased. This is consistent with the Ki data indicating an increase in the affinity of SABA for the uptake site for 5-HT when [Na+] was decreased. The results suggest that there may be two conformational states of the carrier for 5-HT which can be interconverted by changing the concentration of Na+. The affinity of SABA and fluoxetine for these two conformational states is different.
D000818:Animals; D001386:Azides / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D005473:Fluoxetine / Q000494:pharmacology*; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D008968:Molecular Conformation; D010782:Photolysis; D011437:Propylamines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012701:Serotonin / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D012964:Sodium / Q000494:pharmacology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism*
D001386:Azides; D011437:Propylamines; D005473:Fluoxetine; D012701:Serotonin; C046122:3-(2-(4-azidobenzamidino)ethyl)-5-hydroxyindole; D012964:Sodium