Abstract
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).
Highlights
The neurotransmitter 5-hydroxytryptamine (5-HT), known as serotonin, is involved in various physiological functions such as learning, mood and food uptake
The dissociation constant (KD) was calculated as 0.5×10-6 M from the binding curve of glutathione S-transferase (GST)-intracellular loop 3 (iL3). These results indicated that GST-iL3 bound to the im
As the concentration of KKJ00016 increased, the level of cAMP induced by serotonin decreased, and the IC50 value of KKJ00016 in this assay system was calculated about 15 M (Figure 4B). These results indicated that KKJ0016 that could block the interaction between the iL3 of serotonin receptor subtype 6 (5-HT6) and G s, and it prevented the serotonin-induced production of cAMP in the cell transfected with 5-HT6
Summary
The neurotransmitter 5-hydroxytryptamine (5-HT), known as serotonin, is involved in various physiological functions such as learning, mood and food uptake. The receptors for serotonin (5-HT1, 5-HT2, 5-HT3 and 5-HT4) have been identified from pharmacological investigation (Brandley et al, 1986; Bockaert et al, 1990; Baxter et al, 1995; Kilpatrick et al, 1991). Three more families of serotonin receptors (5-HT5, 5-HT6 and 5-HT7) were discovered from molecular biological studies (Ree et al, 1994; Kohen et al, 1996; Jasper et al, 1997). These serotonin receptors, except 5-HT3, belong to G-protein coupled receptors (GPCRs), and they transduce the signal via the interaction with different types of G-proteins. The stimulatory G-protein (Gs) is coupled to 5-HT4, 5-HT6 and 5-HT7 (Hoyer and Martin, 1997), whereas inhibitory G-protein (Gi) to 5-HT1, 5-HT5 (Hoyer and Schoeffter, 1991; Francken et al, 1998)
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