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.