An inhibitory compound against the interaction between G alpha(s) and the third intracellular loop region of serotonin receptor subtype 6 (5-HT6) disrupts the signaling pathway of 5-HT6.
Serotonin receptor subtype 6 (5-HT(6)) is a neurotransmitter receptor, which is involved in various brain functions such as memory and mood. It mediates signaling via the interaction with a stimulatory G-protein. Especially, the third intracellular loop (iL3) of 5-HT(6) and the alpha subunit of stimulatory G protein (G alpha(s)) are responsible for the signaling process of 5-HT(6). Chemical compounds that could inhibit the interaction between the iL3 region of 5-HT(6) and G alpha(s) were screened from a chemical library consisted of 5,600 synthetic compounds. One of the identified compounds bound to G alpha(s) and effectively blocked the interaction between G alpha(s) and the iL3 region of 5-HT(6). The identified compound was further shown to reduce the serotonin-induced accumulation of cAMP in 293T cells transformed with 5-HT(6) cDNA. It also lowered the Ca(2+) efflux induced by serotonin in cells expressing 5-HT(6) and chimeric G alpha(s5/q). These results indicate that the interaction between the iL3 of 5-HT(6) and G alpha(s) can be exploited for screening of regulatory compounds against the signaling pathway of 5-HT(6).
Choi
Yun Hee
YH
Life Sciences Division, Korea Institute of Science and Technology, Seoul 130-650, Korea.
Kang
Hatan
H
Lee
Won Kyu
WK
Kim
Taehyun
T
Rhim
Hyewhon
H
Yu
Yeon Gyu
YG
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002511:Cephalosporins / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000096:biosynthesis; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D015398:Signal Transduction
D002511:Cephalosporins; C522895:KKJ 00016; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C097216:serotonin 6 receptor; D012701:Serotonin; D000242:Cyclic AMP; D019205:GTP-Binding Protein alpha Subunits, Gs; D002118:Calcium