"We tried serotonin and other substrates for the transporter like amphetamines. We found that anything that goes through the transporter blocks this phosphorylation," Blakely said. By blocking the phosphorylation, serotonin and other substrates prevent the transporter from moving off the surface.
"We call it our use-it-or-lose-it model for transport," Blakely said. "If the transporter is not active, it becomes susceptible to other pathways and regulators that pull it off the cell surface. It was a big surprise that the activity of the transporter itself would play such an important role in regulation."
Drugs that block transporter activity -- antidepressants and cocaine -- prevent serotonin from sustaining the transporter at the cell surface. This is a very different action than simply blocking transporter activity to influence the level of neurotransmitter in the synapse.
"We don't understand why antidepressants take a certain period of time to have activity, or why use-dependent changes occur with respect to addiction," Blakely said. "What we're hinting at is that a long term consequence of these drugs occupying the transporter will be an influence on the number of transporters at the cell surface."
Characterizing the signals that participate in the dynamic process of moving transporters on and off the surface opens up possibilities for developing new antidepressant drugs. Such drugs would have the same functional effects as a drug like Prozac, but they would work in an entirely new way -- from the inside of the neuron.
"New antidepressants might manipulate these regulatory pathways that we didn't recognize as being so important before we did these studies," Blakely said.
The research also offers new insight to the actions of psychostimulants like
amphetamines and cocaine. Al
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Contact: Matt Scanlan
matt.scanlan@mcmail.vanderbilt.edu
615-322-4747
Vanderbilt University Medical Center
30-Jul-1999