The novel cellular mechanism of human 5-HT6 receptor through an interaction with Fyn.
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.
Yun
Hyung-Mun
HM
Biomedical Research Center, Korea Institute of Science and Technology, Seoul 136-791, Korea.
Kim
Sunoh
S
Kim
Hyun-Ji
HJ
Kostenis
Evi
E
Kim
Jae Il
JI
Seong
Jae Young
JY
Baik
Ja-Hyun
JH
Rhim
Hyewhon
H
D000339:Affect / Q000502:physiology; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003863:Depression / Q000235:genetics / Q000378:metabolism; D004644:Emotions / Q000502:physiology; D006801:Humans; D008032:Limbic System / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D018909:src Homology Domains / Q000235:genetics
D011985:Receptors, Serotonin; C097216:serotonin 6 receptor; C494957:FYN protein, human; D051076:Proto-Oncogene Proteins c-fyn; D019950:Mitogen-Activated Protein Kinase 1