Dimerization of the 5HT2C Receptor

There is increasing evidence that many GPCRs exist as homodimers and heterodi-mers and that their oligomeric assembly plays functional roles affecting G-protein coupling, downstream signaling, and regulatory processes such as internalization (reviewed in Terrillon and Bouvier 2004). Using fluorescence resonance energy transfer (FRET) combined with confocal microscopy, Herrick-Davis et al. demonstrated that 5-HT2C receptors exist as constitutive homodimers on the plasma membrane of living HEK 293 cells expressing fluorescently tagged 5-HT2C receptors (Herrick-Davis et al. 2004). Further, the same group evaluated the effect of dimerization on receptor function by coexpressing wild-type 5-HT2C receptors with an inactive mutant (S138R) receptor in HEK 293 cells (Herrick-Davis et al. 2005).

It appears that inactive 5-HT2C receptors form nonfunctional heterodimers expressed on the plasma membrane, thus inhibiting wild-type receptor function. Studies of ligand/dimer/G-protein stoichiometry in living HEK 293 cells suggest that one 5-HT2C receptor dimer binds two molecules of ligand, resulting in the activation of one G protein (Herrick-Davis et al. 2005). The 5-HT2C receptor has two distinct dimerization interfaces, one between transmembrane (Tm) helices IV and V, and the other between TM I helices (Mancia et al. 2008). The TM I interface is insensitive to the activation state of the receptor, whereas the IV/V interface is markedly sensitive to the type of ligands bound to the 5-HT2C receptors. Furthermore, the dimer is asymmetrical in its interaction with Gaq protein; activated 5-HT2C receptors also may be able to associate with other GPCRs (Mancia et al. 2008).

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