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 125I- 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 (Ki = 0.25 mM) was tenfold more effective as an inhibitor than harmaline (Ki = 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+ (Km = 50 mM). 45Ca(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.
Kaminsky
S M
SM
Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461.
Levy
O
O
Garry
M T
MT
Carrasco
N
N
D000818:Animals; D001693:Biological Transport, Active; D002243:Carbolines / Q000494:pharmacology*; D002273:Carcinogens / Q000494:pharmacology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002417:Cattle; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D006246:Harmaline / Q000494:pharmacology*; D007700:Kinetics; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D027981:Symporters; D013961:Thyroid Gland / Q000378:metabolism; D000099209:Sodium-Iodide Symporters
D002243:Carbolines; D002273:Carcinogens; D002352:Carrier Proteins; D006246:Harmaline; D008565:Membrane Proteins; D027981:Symporters; D000099209:Sodium-Iodide Symporters; C019133:3-amino-1-methyl-5H-pyrido(4,3-b)indole