Subtle Differences among 5-HTAC, 5-HTAD, and 5-HTAE Receptors Are Revealed by Partial Agonists.

5-HT receptors are members of the Cys-loop family of ligand-gated ion channels, and, like most members of this family, there are multiple subunits that can contribute to functional pentameric receptors. 5-HTA and 5-HTAB receptors have been extensively characterized, but there are few studies on 5-HTAC, 5-HTAD, and 5-HTAE receptors. Here we explore the properties of a range of partial agonists at 5-HTAC, 5-HTAD, and 5-HTAE receptors following expression in Xenopus oocytes. The data show that the characteristics of receptor activation differ in the different heteromeric receptors when they are challenged with 5-HT, m-chlorophenylbiguanide (mCPBG), varenicline, 5-fluorotryptamine (5-FT), or thymol. 5-HT, 5-FT, varenicline, and mCPBG activation of 5-HTAC, 5-HTAD, and 5-HTAE receptors yields similar ECs to homomeric 5-HTA receptors, but maximal responses differ. There are also differences in the levels of potentiation by thymol, which is greater at 5-HTA receptors than 5-HTAB, 5-HTAC, 5-HTAD, or 5-HTAE receptors. Docking thymol into the receptor indicates a different residue in the transmembrane domain could provide an explanation for these data. Overall our study suggests that 5-HTAC, 5-HTAD, and 5-HTAE have distinct pharmacological profiles to those of 5-HTA and 5-HTAB receptors; this is likely related to their distinct roles in the nervous system, consistent with their differential association with various disorders. Thus, these data pave the way for drugs that can specifically target these proteins.