Targeting of the 5-HT1A serotonin receptor to neuronal dendrites is mediated by Yif1B

The 5- HT1A receptor ( 5- HT1AR) is the most extensively characterized serotonin ( 5- HT) receptor mainly because of its involvement in the mode of action of antidepressants. The 5- HT1AR is confined to the somatodendritic domain of central neurons, where it mediates serotonin- evoked hyperpolarization. Our previous studies underlined the role of the short 5- HT1AR C- terminal domain in receptor targeting to dendrites. We used this 17 aa region as bait in a yeast two- hybrid screen, and identified, for the first time, an intracellular protein interacting with the 5- HT1AR. This protein is homologous to the yeast Yif1p, previously implicated in vesicular trafficking between the endoplasmic reticulum ( ER) and the Golgi apparatus, but not yet characterized in mammals. We confirmed 5- HT1AR - Yif1B interaction by glutathione S- transferase pull- down experiments using rat brain extracts and transfected cell lines. Yif1B is highly expressed in the brain, and specifically in raphe 5- HT1AR- expressing neurons. Colocalization of Yif1B and 5- HT1AR was observed in small vesicles involved in transient intracellular trafficking. Last, inhibition of endogenous expression of Yif1B in primary neuron cultures by small interfering RNA specifically prevented the addressing of 5- HT1AR to distal portions of the dendrites, without affecting other receptors, such as sst2A, P2X2, and 5- HT3A receptors. Together, our results provide strong evidence that Yif1B is a member of the ER/ Golgi trafficking machinery, which plays a key role in specific targeting of 5- HT1AR to the neuronal dendrites. This finding opens up new pathways for the study of 5- HT1AR regulation by partner proteins and for the development of novel antidepressant drugs.