A possible role for tyrosine kinases in the regulation of the neuronal dopamine transporter in mouse striatum

Simon, Jay R.; Bare, Dan J.; Ghetti, Bernardino; Richter, Judith A.

doi:10.1016/s0304-3940(97)13479-6

Cited by 33 publications

(30 citation statements)

References 26 publications

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“…Recent evidence that estrogen in the CNS is capable of modulating DA uptake [52], as well as our findings of in vitro CORT effects on DA uptake [40], indicates that endogenous hormones may play an important role in the physiological regulation of the DAT, and perhaps other members of the neurotransmitter transporter family. The present findings along with other in vivo and in vitro findings [38, 45, 53, 54], and see ref. 19] for discussion] suggest that hormonal and second-messener modulation of the amine reuptake transporters may make a critical contribution to the final activity level of the CNS dopaminergic pathway.…”

Section: Discussionsupporting

confidence: 91%

Food Deprivation Decreases mRNA and Activity of the Rat Dopamine Transporter

Brot²,

et al. 1998

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We have hypothesized that the midbrain dopamine (DA) neurons are a target for insulin action in the central nervous system (CNS). In support of this hypothesis, we have previously demonstrated that direct intracerebroventricular infusion of insulin results in an increase in mRNA levels for the DA reuptake transporter (DAT). In this study, 24- to 36-hour food deprivation was used as a model of decreased CNS insulin levels, to test whether DAT mRNA levels, DAT protein concentration or DAT functional activity would be decreased. DAT mRNA levels, assessed by in situ hybridization, were significantly decreased in the ventral tegmental area/substantia nigra pars compacta (VTA/SNc) (77 ± 7% of controls, p < 0.05) of food-deprived (hypoinsulinemic) rats. Binding of a specific high-affinity DAT ligand (¹²⁵I-RTI-121) to membranes from brain regions of fasted or free-feeding rats provided an estimate of DAT protein, which was unchanged in both of the major terminal projection fields, the striatum and nucleus accumbens (NAc). In addition, we utilized the rotating disk electrode voltametry technique to assess possible changes in the function of the DAT in fasting (hypoinsulinemic) rats. The V_max of DA uptake was significantly decreased (87 ± 7% of control, p < 0.05), without a change in the K_m of uptake, in striatum from fasted rats. In vitro incubation with a physiological concentration (1 nM) of insulin resulted in an increase of striatal DA uptake to control levels. We conclude that striatal DAT function can be modulated by fasting and nutritional status, with a contribution by insulin.

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Section: Discussionsupporting

confidence: 91%

Food Deprivation Decreases mRNA and Activity of the Rat Dopamine Transporter

Brot²,

et al. 1998

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“…Possibly, differences in culture conditions explain the differences in findings of the two groups, although as yet they remain unexplained. Simon et al (1997) first reported pharmacological evidence of a role for TK signaling with respect to DAT regulation, with findings of reduced DA uptake in mouse striatal homogenates achieved through a reduction in DA transport V max . Similar, although less potent effects were observed with the TK inhibitor tyrphostin 23.…”

Section: A Pharmacological Evidence For Tyrosine Kinase Modulation Omentioning

confidence: 99%

“…Although in the Annamalai studies of Src-induced elevation of 5-HT uptake in transfected HTR cells Kinase Modulation of Biogenic Amine Transport similar findings were obtained with NET (and DAT, but not taurine transporter) transfected cells. With respect to DAT, Simon et al (1997) failed to detect a phosphoprotein of the size of DAT, as probed by phosphotyrosine immunoblotting methods, after genistein treatment of mouse striatal homogenates, although immunoprecipitation to enrich for DAT was not pursued. Foster et al (2003) also found no reduction in DAT basal phosphorylation when metabolically labeled striatal slices were treated with purified Tyr phosphatase in contrast to efficient dephosphorylation evident with the Ser phosphatase PP1.…”

Section: Evidence Of Tyrosine Phosphorylation Of Monoamine Transpomentioning

confidence: 99%

Kinase-dependent Regulation of Monoamine Neurotransmitter Transporters

Bermingham

Blakely

2016

Pharmacol Rev

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“…The role of tyrosine phosphorylation in regulating GABA transporter function has yet to be elucidated, although there is reasonable evidence to suggest that this form of regulation of the transporter might occur: (i) protein phosphorylation of tyrosine residues acutely regulates neurotransmitter receptors (18) and ion channels (19 -22); (ii) the primary amino acid sequence of the rat brain GABA transporter GAT1 contains five putative intracellular tyrosine phosphorylation sites (23); and (iii) pharmacological manipulation of tyrosine kinases acutely regulates serotonin and dopamine transporters (24,25), although the mechanism underlying the modulation is not known. Long term regulation of serotonin transport by tyrosine kinases may be because of alterations in transporter mRNA levels (26).…”

Section: ␥-Aminobutyric Acid (Gaba)mentioning

confidence: 99%

Functional Regulation of γ-Aminobutyric Acid Transporters by Direct Tyrosine Phosphorylation

Law

Stafford

Quick

2000

Journal of Biological Chemistry

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Tyrosine phosphorylation regulates multiple cell signaling pathways and functionally modulates a number of ion channels and receptors. Neurotransmitter transporters, which act to clear transmitter from the synaptic cleft, are regulated by multiple second messenger pathways that exert their effects, at least in part, by causing a redistribution of the transporter protein to or from the cell surface. To test the hypothesis that tyrosine phosphorylation affects transporter function and to determine its mechanism of action, we examined the regulation of the rat brain ␥-aminobutyric acid (GABA) transporter GAT1 expressed endogenously in hippocampal neurons and expressed heterologously in Chinese hamster ovary cells. Inhibitors of tyrosine kinases decreased GABA uptake; inhibitors of tyrosine phosphatases increased GABA uptake. The decrease in uptake seen with tyrosine kinase inhibitors was correlated with a decrease in tyrosine phosphorylation of GAT1 and resulted in a redistribution of the transporter from the cell surface to intracellular locations. A mutant GAT1 construct that was refractory to tyrosine phosphorylation could not be regulated by tyrosine kinase inhibitors. Activators of protein kinase C, which are known to cause a redistribution of GAT1 from the cell surface, were additive to the effects of tyrosine kinase inhibitors suggesting that multiple signaling pathways control transporter redistribution. Application of brain-derived neurotrophic factor, which activates receptor tyrosine kinases, up-regulated GAT1 function suggesting one potential trigger for the cellular regulation of GAT1 signaling by tyrosine phosphorylation. These data support the hypothesis that transporter expression and function is controlled by the interplay of multiple cell signaling cascades. ␥-Aminobutyric acid (GABA)1 is the predominant inhibitory neurotransmitter in the central nervous system and plays a pivotal role in the balance between neuronal excitation and inhibition. The time course of neurotransmitter in the synaptic cleft is one determinant of synaptic transmission, and its removal from the cleft via specific transporters provides an efficient mechanism for termination of signaling. GABA transporters (GATs) are located on the plasma membrane of neurons and glia (1) and function to remove GABA through co-transport of ions down their electrochemical gradient (2). Demonstration of a physiological role for GABA transporters comes from experiments involving specific GABA uptake inhibitors; these inhibitors affect both GABA A and GABA B receptor-mediated synaptic signaling (3-5). GABA transporters also play a pathophysiological role in temporal lobe epilepsy (6) and are the targets of pharmacological interventions in epilepsy (7). An important property of GABA transporters, and neurotransmitter transporters in general, is their ability to be functionally regulated by a wide variety of signaling cascades (for review, see Refs. 8 and 9). Functional modulation occurs in part through second messengers such as kinases, phosphatas...

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A possible role for tyrosine kinases in the regulation of the neuronal dopamine transporter in mouse striatum

Cited by 33 publications

References 26 publications

Food Deprivation Decreases mRNA and Activity of the Rat Dopamine Transporter

Food Deprivation Decreases mRNA and Activity of the Rat Dopamine Transporter

Kinase-dependent Regulation of Monoamine Neurotransmitter Transporters

Functional Regulation of γ-Aminobutyric Acid Transporters by Direct Tyrosine Phosphorylation

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