HUMAN SEROTONIN TRANSPORTER - REGULATION BY THE NEUROPROTECTIVE AGENTAURINTRICARBOXYLIC ACID AND BY EPIDERMAL GROWTH-FACTOR

The influence of aurintricarboxylic acid (ATA), a neuroprotective comp ound, on the serotonin transporter expressed in JAR human placental ch oriocarcinoma cells was investigated. Treatment of the cells with ATA for 16 h led to a significant stimulation of the serotonin transporter activity. This effect was not observed, however, when the treatment w as done for 1-2 h. The stimulatory effect was associated with an incre ase in the maximal velocity of the transport process with no significa nt change in the Michaelis-Menten constant. Northern blot hybridizatio n revealed that ATA treatment caused a marked increase in the steady-s tate levels of serotonin transporter-specific transcripts. Treatment o f the cells with ATA was found to increase tyrosine phosphorylation of a 180-kDa protein. The phosphotyrosine content of a protein of a simi lar molecular size increased dramatically when the cells were exposed to epidermal growth factor (EGF), suggesting that this protein may be the EGF receptor. Treatment of the cells with EGF for 24 h could repro duce the stimulatory effects of ATA on the serotonin transporter activ ity, the maximal velocity of the transport process, and the steady-sta te levels of the transporter-specific mRNAs. Genistein, a tyrosine kin ase inhibitor, was able to block the stimulatory effect of ATA and EGF , It is concluded that EGF increases the serotonin transporter express ion in JAR cells and that the neuroprotective compound ATA produces si milar effects on the transporter most likely by activating the EGF rec eptor through tyrosine phosphorylation.