Activation, internalization, and recycling of the serotonin 2A receptor by dopamine.
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.
Bhattacharyya
Samarjit
S
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.
Raote
Ishier
I
Bhattacharya
Aditi
A
Miledi
Ricardo
R
Panicker
Mitradas M
MM
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*
D044402:Receptor, Serotonin, 5-HT2A; D004298:Dopamine