Modulation of monoamine transporters by common biogenic amines via trace amine-associated receptor 1 and monoamine autoreceptors in human embryonic kidney 293 cells and brain synaptosomes

In brain monoaminergic systems, common biogenic amines, including dopamine, norepinephrine, and serotonin, serve as neurotransmitters. Monoamine autoreceptors provide feedback regulation in neurotransmitter release, and monoamine transporters clear the released neurotransmitters to control synaptic signaling. Recently, trace amine-associated receptor 1 (TAAR1) has been found to be expressed in brain monoaminergic nuclei and activated by common biogenic amines in vitro. This study used transfected cells and brain synaptosomes to evaluate the interaction of common biogenic amines with TAAR1 and monoamine autoreceptors and explore their modulatory effects on monoamine transporters. We confirmed that TAAR1 was activated by dopamine, norepinephrine, and serotonin and demonstrated that TAAR1 signaling was attenuated by monoamine autoreceptors at exposure to dopamine, norepinephrine, and serotonin. In transfected cells, TAAR1 in response to dopamine, norepinephrine, and serotonin significantly inhibited uptake and promoted efflux of [H-3] dopamine, [H-3] norepinephrine, and [H-3] serotonin, respectively, whereas the monoamine autoreceptors, D2s, alpha(2A), and 5-HT1B enhanced the uptake function under the same condition. In brain synaptosomes, dopamine, norepinephrine, and serotonin significantly altered the uptake and efflux of [H-3] dopamine, [H-3] norepinephrine, and [H-3] serotonin, respectively, when the monoamine autoreceptors were blocked. By comparing the effects of dopamine, norepinephrine, and serotonin in monkey and wild-type mouse synaptosomes to their effects in TAAR1 knockout mouse synaptosomes, we deduced that TAAR1 activity inhibited uptake and promoted efflux by monoamine transporters and that monoamine autoreceptors exerted opposite effects. These data provide the first evidence that common biogenic amines modulate monoamine transporter function via both TAAR1 and monoamine autoreceptors, which may balance monoaminergic activity.