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

Abstract

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]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.Common biogenic amines are neurotransmitters in brain that are synthesized and packaged in monoaminergic neurons and released into synaptic clefts to interact with presynaptic and postsynaptic receptors. Monoamine transporters, including dopamine transporter (DAT), norepinephrine transporter (NET), and serotonin transporter (SERT), clear the released neurotransmitters to terminate neural signaling (Uhl and Johnson, 1994;Masson et al., 1999) and are functionally or dynamically regulated by various chemicals, including psychostimulants and antidepressants (Sulzer et al., 1995;Gutman and Owens, 2006;Fleckenstein et al., 2007). Aberrant transport of common biogenic amines by monoamine transporters in brain is associated with a variety of neuropsychiatric disorders/diseases, such as anxiety, depression, Parkinson's disease, schizophrenia, suicide, and drug abuse/addiction (Klimek et al., 1997;Arango et al., 2002;Schmitt et al., 2006;Serretti et al., 2006). Monoamine autoreceptors, residing on the presynaptic membranes of monoaminergic neurons, monitor and respond to the released common biogenic amines to provide feedback regulation of Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.107.135079. ABBREVIATIONS:DAT, dopamine transporter; 5-HT 1A and 5-HT 1B , subtype A and B of serotonin receptor 1; ␣ 2A and ␣ 2B , subtype A and B of alpha adrenal rec...

Modulation by Trace Amine-Associated Receptor 1 of Experimental Parkinsonism, l-DOPA Responsivity, and Glutamatergic Neurotransmission

“…However, after MFB 6-OHDA injections, a near-complete loss of TH levels was found in both genotypes, indicating that the partial survival of dopaminergic neurons is required for this effect of TAAR1. Consistent with our finding of enhanced DAT levels in TAAR1 KO mice, previous in vitro studies in brain synaptosomes and transfected cells have reported that activation of TAAR1 internalizes DAT from the cell membrane, inhibits dopamine reuptake, and enhances dopamine efflux via DAT reversal Xie et al, 2008), However, because 6-OHDA elicits its neurotoxic effects by entering the neuron via DAT, the finding of a more pronounced reduction of TH in TAAR1 KO compared with WT mice was unexpected. These studies were extended to experiments examining the effects of a TAAR1 agonist, RO5166017, on reduction of DAT by intrastriatal 6-OHDA administration in WT mice.…”

“…It seems that TAAR1 is expressed, not only in nerve cells, but also in glia because a recent study reported that TAAR1 activation on human astrocytes can decrease glutamate clearance in vitro via downregulation of EAAT-2 expression (Cisneros and Ghorpade, 2014). There is also a need for more precise information on the subcellular localization of TAAR1 in intact cells, especially because several experiments in transfected HEK293 cells have indicated that TAAR1 is mainly localized intracellularly (Bunzow et al, 2001;Miller et al, 2005;Xie et al, , 2008. Future studies are needed to determine whether a cytosolic localization of TAAR1 causes specific effects on intracellular signaling with relevance to neurotransmitter release.…”

Role of TAAR1 within the Subregions of the Mesocorticolimbic Dopaminergic System in Cocaine-Seeking Behavior

“…TAAR1 mRNA expression in the mesocorticolimbic system TAAR1 mRNA has been found in the limbic system, cortices, and monoaminergic system of the mammalian brain (Borowsky et al, 2001;Bunzow et al, 2001;Miller et al, 2005;Lindemann et al, 2008;Xie et al, 2008;Espinoza et al, 2015a). Consistent with this, using real-time PCR method, the present study also showed that TAAR1 mRNA was expressed in the VTA, SN, mPFC, NAc, and amygdala.…”

Oligomerization of GPCRs involved in endocrine regulation

“…There are few examples that support the notion of a direct GPCR/channel (Yekkirala 2013) or GPCR/transporter interactions, e.g. the observed interplay between the ADRB2, GLUT4 and melatonin 1 receptor/Cav 2.2 (Dehvari et al 2012, Benleulmi-Chaachoua et al 2016, or modulation of monoamine transporters by common biogenic amines via the TAAR1 (Xie et al 2008). Altogether, this raises the possibility that an association between different proteins and GPCRs should be of importance due to a fast mutual or synergistic influence on functional properties.…”