Heterodimers 5HT2C and 5HT2A

To date, there are no published studies reporting the heterodimerization of 5-HT2C receptors with other members of the serotonin receptor family. Of the 13 different serotonin receptors identified in humans, the 5-HT2A receptor is structurally the most similar to the 5-HT2C receptor, and they are coexpressed in regions such as the hippocampus and cortex. Do 5-HT2C receptors form heterodimers with 5-HT2A receptors? Given the large body of evidence suggesting that heterodimers can have unique signaling properties, this is an appropriate question to ask. In preliminary studies, we have observed cotrafficking of CFP- and YFP-tagged 5-HT2C and 5-HT2A receptors in transfected HEK 293 cells. In addition, we have observed co-staining of 5-HT2C and 5-HT2A receptors within individual primary hippocampal neurons (unpublished observations). During these studies, we identified commercially available antibodies with good specificity for 5-HT2C (Santa Cruz, C-20) and 5-HT2A (Calbiochem, N22-41) receptors. When tested in 5-HT2C and 5-HT2A stable cells lines, no cross-reactivity was observed with either antibody. Coimmunoprecipitation of native 5-HT2C and 5-HT2A receptors from primary hip-pocampal cultures along with detailed ultra structural microscopy studies would provide a good starting point for exploring the possible existence of 5-HT2C-5-HT2A heterodimers in vivo.

While many studies have reported the formation of GPCR heterodimers with unique ligand binding and signaling properties, very few studies have been able to demonstrate the existence of the putative heterodimers in vivo. Dimerization is believed to occur during receptor biosynthesis within the ER. Therefore, heterodimerization would require the coordinated synthesis of the two different receptor species. Thus, if heterodimerization of two different GPCR is to take place, then factors or signals that regulate or turn on the translation of each mRNA species must occur simultaneously, and protein synthesis of each protein species must occur within close enough proximity to allow the preferential formation of heterodimers over the formation of homodimers. A good example involves Pj- and P2-adrenergic receptors that have been reported to form het-erodimers in recombinant cells (Mercier et al. 2002). While the heterodimers display different functional properties in recombinant cells, near-field scanning microscopy studies reveal that native Pj- and P2-adrenergic receptors in cardio-myocytes traffic in different membrane microdomains, inconsistent with the formation of heterodimers in vivo (Ianoul et al. 2005). Therefore, caution should be exercised in interpreting the physiological significance of heterodi-merization studies performed in recombinant cells, even if there is evidence that both receptor species are coexpressed within a given cell type in vivo.

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