Abstract
The human 5-HT(6) receptor (5-HT(6)R) is one of the latest cloned receptors among the known 5-HT receptors. Its abundant distribution in the limbic region, which participates in the control of mood and emotion and is involved in nervous system diseases such as depression and Alzheimer disease, has caused it to generate much interest. However, the cellular mechanisms of 5-HT(6)R are poorly understood. In the present study we found, using a yeast two-hybrid assay, that the carboxyl-terminal region of 5-HT(6)R interacts with the Fyn-tyrosine kinase. We also determined using a glutathione S-transferase pulldown assay that this interaction was mediated through the SH3 domain of Fyn and confirmed this by co-immunoprecipitation assays in two different transfected cell lines as well as in adult rat brains. Immunocyto(histo)chemistry also showed prominent co-localization between 5-HT(6)R and Fyn in transfected cells and a similar distribution between 5-HT(6)R and Fyn in the rat brain. Based on this interaction, we further examined the modulation of 5-HT(6)R by Fyn and vice versa. In addition, we demonstrated that the activation of 5-HT(6)R activated the extracellular signal-regulated kinase1/2 via an Fyn-dependent pathway. These findings suggest that Fyn may play an important role in 5-HT(6)R- mediated signaling pathways in the central nervous system.
Highlights
Diverse physiological responses through at least 16 different receptors which are subdivided into 7 distinct subfamilies, the 5-HT1–7 receptors
After screening the human brain cDNA library, we identified that Fyn-tyrosine kinase interacted with the carboxyl terminus (CT) of 5-HT6 receptor (5-HT6R)
We found that Fyn acts as a 5-HT6R-binding protein using a yeast two-hybrid assay and that 5-HT6R and Fyn are present as a protein complex in transfected cells and adult rat brains using co-immunoprecipitation binding assays
Summary
Diverse physiological responses through at least 16 different receptors which are subdivided into 7 distinct subfamilies, the 5-HT1–7 receptors. We determined using a glutathione S-transferase pulldown assay that this interaction was mediated through the SH3 domain of Fyn and confirmed this by co-immunoprecipitation assays in two different transfected cell lines as well as in adult rat brains.
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