title: Activation, internalization, and recycling of the serotonin 2A receptor by dopamine.
abstract: Serotonergic and dopaminergic systems, and their functional interactions, have been implicated in the pathophysiology of various CNS disorders. Here, we use recombinant serotonin (5-HT) 2A (5-HT2A) receptors to further investigate direct interactions between dopamine and 5-HT receptors. Previous studies in Xenopus oocytes showed that dopamine, although not the cognate ligand for the 5-HT2A receptor, acts as a partial-efficacy agonist. At micromolar concentrations, dopamine also acts as a partial-efficacy agonist on 5-HT2A receptors in HEK293 cells. Like 5-HT, dopamine also induces receptor-internalization in these cells, although at significantly higher concentrations than 5-HT. Interestingly, if the receptors are first sensitized or "primed" by subthreshold concentrations of 5-HT, then dopamine-induced internalization occurs at concentrations approximately 10-fold lower than when dopamine is used alone. Furthermore, unlike 5-HT-mediated internalization, dopamine-mediated receptor internalization, alone, or after sensitization by 5-HT, does not depend on PKC. Dopamine-internalized receptors recycle to the surface at rates similar to those of 5-HT-internalized receptors. Our results suggest a previously uncharacterized role for dopamine in the direct activation and internalization of 5-HT2A receptors that may have clinical relevance to the function of serotonergic systems in anxiety, depression, and schizophrenia and also to the treatment of these disorders.
authors.affiliation: National Centre for Biological Sciences, Tata Institute of Fundamental Research, University of Agricultural Sciences-Gandhi Krishi Vignana Kendra Campus, Bellary Road, Bangalore-560065, Karnataka, India.
authors.forename: Samarjit
authors.initials: S
authors.lastname: Bhattacharyya
authors.forename: Ishier
authors.initials: I
authors.lastname: Raote
authors.forename: Aditi
authors.initials: A
authors.lastname: Bhattacharya
authors.forename: Ricardo
authors.initials: R
authors.lastname: Miledi
authors.forename: Mitradas M
authors.initials: MM
authors.lastname: Panicker
mesh_terms: D000818:Animals; D002460:Cell Line; D004298:Dopamine / Q000502:physiology*; D006801:Humans; D021381:Protein Transport / Q000502:physiology; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*
chemical_list: D044402:Receptor, Serotonin, 5-HT2A; D004298:Dopamine