INHIBITION OF THE NA+/I- SYMPORTER BY HARMALINE AND 3-AMINO-1-METHYL-5H-PYRIDO(4,3-B)INDOLE ACETATE IN THYROID-CELLS AND MEMBRANE-VESICLES

Novel inhibitors of the Na+/I- symporter were identified using rat-thyroid-derived FRTL-5 cells and sealed vesicles from calf thyroid as model systems. Na+-dependent I-125- uptake was inhibited by the hallucinogenic drug harmaline and by a chemically related convulsive agent, 3-amino-1-methyl-5H-pyrido(4,3-b)indole acetate (TRP-P-2). TRP-P-2 (K(i) = 0.25 mM) was tenfold more effective as an inhibitor than harmaline (K(i) = 4.0 mM). Inhibition by TRP-P-2 was competitive with respect to Na+ and was fully reversible. Although TRP-P-2 is a relatively low-affinity inhibitor, its affinity for the Na+ site of the Na+/I-symporter is over 100 times higher than that of Na+ (K(m) = 50 mM). Ca-45(2+)-efflux rates in calf thyroid membrane vesicles were not affected by TRP-P-2, indicating that membrane integrity is not disrupted by the drug. These findings show that TRP-P-2 may be a potentially useful tool for the identification and characterization of the Na+/I- symporter.