Conclusion

The 5-HT2C receptor couples to a large array of signal transduction pathways. This pleiotropic coupling results from the activation of at least three distinct families of heterotrimeric G proteins, from physical interactions of numerous regulatory proteins with intracellular portions of the receptor, from receptor dimerization, and from cell- and ligand-specific effects. In that regard, the recently described phenomenon of "functional selectivity" implies that ligands induce unique, ligand-specific receptor conformations that frequently can result in differential activation of signal transduction pathways associated with that particular receptor. This differential activation may be expressed as differences in intrinsic activity and/or potency at one signaling pathway versus another that are not due to differences in affinity at the mediating receptor. This phenomenon has been observed for several families of GPCRs including serotonergic receptors (Urban et al. 2007). The 5HT2C receptor can generate differential intracellular signals in an agonist-dependent manner, as evidenced in both "classical" G-protein-mediated pathways and more complex pathways such as ERK1/2 activation. This pleiotropic coupling to multiple intracellular pathways suggests that the 5HT2C receptor is capable of agonist-directed trafficking of signals. Moreover, the complexity of the 5-HT2C receptor system, with its multiple receptor variants, activation of multiple G proteins, and modulation of both G-protein-dependent and G-protein-independent signaling pathways, suggests that ligand-specific effects can fine tune those pleiotropic coupling signals.

Acknowledgements The authors were supported by grants from the Department of Veterans Affairs (Merit Awards and a REAP Award to Maria N. Garnovskaya (MNG) and John R. Raymond (JRR)), the National Institutes of Health (DK52448 and GM63909 to JRR), AHA (GIA 0655445U to MNG), and a laboratory endowment jointly supported by the M.U.S.C. Division of Nephrology and Dialysis Clinics, Incorporated (JRR).

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