Heterodimers of serotonin receptor subtypes 2 are driven by 5-HT protomers.

The serotonin receptor subtypes 2 comprise 5-HT, 5-HT, and 5-HT, which are Gα-coupled receptors and display distinct pharmacological properties. Although co-expressed in some brain regions and involved in various neurological disorders, their functional interactions have not yet been studied. We report that 5-HT receptors can form homo- and heterodimers when expressed alone or co-expressed in transfected cells. Co-immunoprecipitation and bioluminescence resonance energy transfer studies confirmed that 5-HT receptors interact with either 5-HT or 5-HT receptors. Although heterodimerization with 5-HT receptors does not alter 5-HT Gα-dependent inositol phosphate signaling, 5-HT or 5-HT receptor-mediated signaling was totally blunted. This feature can be explained by a dominance of 5-HT on 5-HT and 5-HT receptor binding; in 5-HT-containing heterodimers, ligands bind and activate the 5-HT protomer exclusively. This dominant effect on the associated protomer was also observed in neurons, supporting the physiological relevance of 5-HT receptor heterodimerization Accordingly, exogenous expression of an inactive form of the 5-HT receptor in the locus ceruleus is associated with decreased 5-HT-dependent noradrenergic transmission. These data demonstrate that 5-HT receptors can form functionally asymmetric heterodimers and that must be considered when analyzing the physiological or pathophysiological roles of serotonin in tissues where 5-HT receptors are co-expressed.