Mechanisms underlying the effects of amphetamine on particulate PKC activity

Giambalvo, Cecilia T.

doi:10.1002/syn.10289

Cited by 26 publications

(23 citation statements)

References 48 publications

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“…PKC-dependent phosphorylation is known to play a key role in the functional regulation of the dopamine transporter by methamphetamine. Methamphetamine increases striatal PKC activity (Giambalvo, 2004), which in turn leads to down-regulation of dopamine transporter function (Zhang et al, 1997). Both methamphetamine-induced phosphorylation and down-regulation of the dopamine transporter are prevented by PKC inhibition in striatal synaptosomes (Sandoval et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

A Receptor Mechanism for Methamphetamine Action in Dopamine Transporter Regulation in Brain

Xie

Miller²

2009

J Pharmacol Exp Ther

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This study reveals a novel receptor mechanism for methamphetamine action in dopamine transporter (DAT) regulation. Trace amine-associated receptor 1 (TAAR1) is expressed in brain dopaminergic nuclei and is activated by methamphetamine in vitro. Here, we show that methamphetamine interaction with TAAR1 3 H]dopamine (10 nM) in a TAAR1-dependent manner. In DAT biotinylation assays using the same cell and synaptosome preparations, we observed that 1 M methamphetamine induced DAT internalization in a TAAR1-dependent manner. All these TAAR1-mediated effects of methamphetamine were blocked by the protein kinase inhibitors H89 [N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline] and/or 2-{8-[(dimethylamino) methyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-3-yl}-3-(1-methylindol-3-yl)maleimide (Ro32-0432), suggesting that methamphetamine interaction with TAAR1 triggers cellular phosphorylation cascades and leads to the observed effects of methamphetamine on DAT. These findings demonstrate a mediatory role of TAAR1 in methamphetamine action in DAT regulation and implicate this receptor as a potential target of therapeutics drugs for methamphetamine addiction.

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Section: Discussionmentioning

confidence: 99%

A Receptor Mechanism for Methamphetamine Action in Dopamine Transporter Regulation in Brain

Xie

Miller²

2009

J Pharmacol Exp Ther

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“…The amphetamine-induced activation of PKC involves activation of phospholipase C and Na ϩ /Ca 2ϩ exchange (38). Further, amphetamine can increase intracellular Ca 2ϩ (14,15).…”

Section: Effect Of Pkc Inhibitors On Amphetamine-stimulated Do-mentioning

confidence: 99%

Regulation of Amphetamine-stimulated Dopamine Efflux by Protein Kinase C β

Johnson

Guptaroy

Lund

et al. 2005

Journal of Biological Chemistry

129

167

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Evidence suggests that protein kinase C (PKC) and intracellular calcium are important for amphetaminestimulated outward transport of dopamine in rat striatum. In this study, we examined the effect of select PKC isoforms on amphetamine-stimulated dopamine efflux, focusing on Ca 2؉ -dependent forms of PKC. Efflux of endogenous dopamine was measured in superfused rat striatal slices; dopamine was measured by high performance liquid chromatography. The non-selective classical PKC inhibitor Gö 6976 inhibited amphetamine-stimulated dopamine efflux, whereas rottlerin, a specific inhibitor of PKC␦, had no effect. A highly specific PKC␤ inhibitor, LY379196, blocked dopamine efflux that was stimulated by either amphetamine or the PKC activator, 12-O-tetradecanoylphorbol-13-acetate. None of the PKC inhibitors significantly altered [3 H]dopamine uptake. PKC␤ I and PKC␤ II , but not PKC␣ or PKC␥, were coimmunoprecipitated from rat striatal membranes with the dopamine transporter (DAT). Conversely, antisera to PKC␤ I and PKC␤ II but not PKC␣ or PKC␥ were able to co-immunoprecipitate DAT. Amphetamine-stimulated dopamine efflux was significantly enhanced in hDAT-HEK 293 cells transfected with PKC␤ II as compared with hDAT-HEK 293 cells alone, or hDAT-HEK 293 cells transfected with PKC␣ or PKC␤ I . These results suggest that classical PKC␤ II is physically associated with DAT and is important in maintaining the amphetamine-stimulated outward transport of dopamine in rat striatum.

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“…Similar results were obtained using confocal imaging of single cells expressing the human norepinephrine transporter (DiPace et al, 2003). At low concentrations of AMPH, extracellular Ca 2ϩ might enter the HEK cells through voltage-dependent Ca 2ϩ channels (Berjukow et al, 1996) or by Na ϩ /Ca 2ϩ exchange (Giambalvo, 2004). The blockade by cocaine of this effect of AMPH delineates this response as DAT-mediated.…”

Section: Intracellular Camentioning

confidence: 99%

Intracellular Ca²⁺Regulates Amphetamine-Induced Dopamine Efflux and Currents Mediated by the Human Dopamine Transporter

et al. 2004

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Although it is clear that amphetamine-induced dopamine (DA) release mediated by the dopamine transporter (DAT) is integral to the behavioral actions of this psychostimulant, the mechanism of this release is not clear. In this study, we explored the requirement for intracellular Ca 2ϩ in amphetamine-induced DA efflux and currents mediated by the human DAT. The patchclamp technique in the whole-cell configuration was used on Na ϩ and DA-preloaded human embryonic kidney 293 cells stably transfected with the human DAT (hDAT cells). Chelation of intracellular Ca 2ϩ by inclusion of 50 M BAPTA in the wholecell pipette reduced the voltage-dependent amphetamine-induced hDAT current, with the greatest effect seen at positive voltages. Likewise, 1,2-bis(2-aminophenoxy)ethane-N,N,NЈ,NЈ-tetraacetic acid (BAPTA) reduced amphetamine-induced DA efflux as measured by amperometry. Furthermore, preincubation of the cells with 50 M BAPTA acetoxy methyl ester (AM) or thapsigargin also blocked amphetamine-induced release of preloaded N-methyl-4-[ 3 H]phenylpyridinium from superfused hDAT cells. BAPTA-AM also reduced DA release from striatal synaptosomes. Amphetamine also led to an increase in intracellular Ca 2ϩ that was blocked by prior treatment with 5 M thapsigargin or 10 M cocaine. These studies demonstrate that amphetamine-induced DAT-mediated currents and substrate efflux require internal Ca 2ϩ and that amphetamine can stimulate dopamine efflux by regulating cytoplasmic Ca 2ϩ levels through its interaction with DAT.The plasmalemmal dopamine transporter, DAT, is essential for regulation of synaptic levels of dopamine (DA). Although the primary physiological function of DAT is to clear DA from the synapse through reuptake, DAT can also mediate DA efflux. As hypothesized for other gated carriers, the function of DAT seems to depend on conformational changes that alternately expose extracellular and intracellular substrate binding sites (Rudnick and Clark, 1993;Abramson et al., 2003). Thus, after transport and dissociation of substrate, the "inward-facing" conformation of DAT is able to bind cytoplasmic DA and carry it to the outside. DA efflux is most apparent in response to a substrate such as amphetamine (AMPH). Because the locomotor and reinforcing effects of AMPH are a result of its ability to release DA into the synapse (Seiden et al., 1993;Giros et al., 1996;Koob and Nestler, 1997), AMPH-induced DA efflux has been highly investigated. AMPH increases the prevalence of the inwardfacing conformation of the plasmalemmal catecholamine transporter (Langeloh et al., 1987), inhibits monoamine oxidase activity, blocks the vesicular transporter (VMAT2), and disrupts the vesicular proton gradient, making more cytoplasmic DA available to the inward-facing DAT (Seiden et al., 1993;Sulzer et al., 1995). Emerging evidence, however, indicates that AMPH-mediated DA efflux does not rely exclusively on the ability of AMPH to increase the availability of inward

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Mechanisms underlying the effects of amphetamine on particulate PKC activity

Cited by 26 publications

References 48 publications

A Receptor Mechanism for Methamphetamine Action in Dopamine Transporter Regulation in Brain

A Receptor Mechanism for Methamphetamine Action in Dopamine Transporter Regulation in Brain

Regulation of Amphetamine-stimulated Dopamine Efflux by Protein Kinase C β

Intracellular Ca²⁺Regulates Amphetamine-Induced Dopamine Efflux and Currents Mediated by the Human Dopamine Transporter

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Mechanisms underlying the effects of amphetamine on particulate PKC activity

Cited by 26 publications

References 48 publications

A Receptor Mechanism for Methamphetamine Action in Dopamine Transporter Regulation in Brain

A Receptor Mechanism for Methamphetamine Action in Dopamine Transporter Regulation in Brain

Regulation of Amphetamine-stimulated Dopamine Efflux by Protein Kinase C β

Intracellular Ca2+Regulates Amphetamine-Induced Dopamine Efflux and Currents Mediated by the Human Dopamine Transporter

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Intracellular Ca²⁺Regulates Amphetamine-Induced Dopamine Efflux and Currents Mediated by the Human Dopamine Transporter