MUTATIONS OF TRANSMEMBRANE-IV AND TRANSMEMBRANE-V SERINES INDICATE THAT ALL TRYPTAMINES DO NOT BIND TO THE RAT 5-HT2A RECEPTOR IN THE SAME MANNER

Two mutations of the rat serotonin 5-HT2A receptor were made, expresse d and examined for their ability to bind and be stimulated by certain tryptamines as well as their ability to bind antagonists. Mutation of Ser(207) to an Ala (S207A) resulted in no substantial changes in bindi ng of either 5-HT2A antagonists or agonists. In contrast, mutation of Ser(239) to an Ala (S239A) resulted in significant changes in the 5-HT 2A receptor with some but not all agonists and antagonists examined. S pecifically, 5-HT had decreased affinity for the S239A mutated 5-HT2A receptor, showing over a IO-fold decrease in receptor-binding displace ment, while still being capable of stimulating IP3 formation. However, the agonists tryptamine, 5-methoxytryptamine (5-MeOT), and N-1-isopro pyl-5-methoxytryptamine; and the antagonists ketanserin, LY 86057, and LY 53857 were significantly less affected by a S239A mutation. These results suggest that while 5-HT might have a direct interaction with t he Ser(239) of the 5-HT2A receptor, tryptamine and 5-MeOT interact wit h this receptor in a different manner. (C) 1997 Elsevier Science B.V.