Heterodimers of serotonin receptor subtypes 2 are driven by 5-HT_2C protomers

The serotonin receptor subtypes 2 comprise 5-HT_2A, 5-HT_2B, and 5-HT_2C, which are Gα_q-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-HT₂ 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_2C receptors interact with either 5-HT_2A or 5-HT_2B receptors. Although heterodimerization with 5-HT_2C receptors does not alter 5-HT_2C Gα_q-dependent inositol phosphate signaling, 5-HT_2A or 5-HT_2B receptor-mediated signaling was totally blunted. This feature can be explained by a dominance of 5-HT_2C on 5-HT_2A and 5-HT_2B receptor binding; in 5-HT_2C-containing heterodimers, ligands bind and activate the 5-HT_2C protomer exclusively. This dominant effect on the associated protomer was also observed in neurons, supporting the physiological relevance of 5-HT₂ receptor heterodimerization in vivo Accordingly, exogenous expression of an inactive form of the 5-HT_2C receptor in the locus ceruleus is associated with decreased 5-HT_2A-dependent noradrenergic transmission. These data demonstrate that 5-HT₂ receptors can form functionally asymmetric heterodimers in vitro and in vivo that must be considered when analyzing the physiological or pathophysiological roles of serotonin in tissues where 5-HT₂ receptors are co-expressed.