Dopamine D2 receptor activation increases vesicular dopamine uptake and redistributes vesicular monoamine transporter-2 protein

Truong, Jannine G.; Newman, Amy Hauck; Hanson, Glen R.; Fleckenstein, Annette E.

doi:10.1016/j.ejphar.2004.09.049

Cited by 43 publications

(33 citation statements)

References 27 publications

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“…A recent study in PC12 PCC cell line showed that a D 2 agonist (bromocriptine) displays an inhibitory effect on the 3 H dopamine uptake through VMAT1/2 in these cells (Izumi et al 2008). However, for the rat striatum, other authors (Brown et al 2001, Truong et al 2004 showed that another D 2 agonist (quinpirole) stimulates the uptake of 3 H dopamine. VMAT1/2 expression is not the only determinant for a positive MIBG/F-DOPA imaging.…”

Section: Discussionmentioning

confidence: 98%

Expression of somatostatin receptors, dopamine D2 receptors, noradrenaline transporters, and vesicular monoamine transporters in 52 pheochromocytomas and paragangliomas

Saveanu¹,

Mureşan²,

Micco³

et al. 2011

Endocrine Related Cancer

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While somatostatin receptors (sst), through somatostatin-radiolabeled analogs, are used, mainly in second line, in the diagnosis and treatment of pheochromocytomas (PCC) and paragangliomas (PGL), the clinical significance of dopamine receptor subtype 2 (D 2 ) in PCC/PGL is unknown. Indeed, radiolabeled dopamine (DA) analogs such as fluorine 18 ( 18 F)-DA, used for positron emission tomography in PCC localization, are mainly correlated to the presence of noradrenaline transporter (NAT) and vesicular monoamine transporters (VMAT) but not to D 2 . The aim of this study was to quantitate D 2 and sst expression in 52 PCC/PGL and to compare it with that of 35 gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Quantitative RT-PCR of sst 1-3 and sst 5 , D 2 , NAT, VMAT1/2 was performed in all tumors, while immunohistochemistry analysis of sst 2 and D 2 was performed in seven tumors. D 2 mRNA was expressed in all PCC/PGL. Mean expression was significantly higher in PCC/PGL than in GEP-NETs (4.8 vs 0.5 copy/copy b-glucuronidase (Gus)). sst 2 and sst 1 were expressed in most PCC/PGL, with sst 2 -dominant expression (mean mRNA: 1.6 vs 0.4 copy/copy b-Gus). sst 2 expression level was similar to that of GEP-NETs, whereas sst 5 expression level was significantly lower (0.12 vs 0.78 copy/copy b-Gus). Our study evidenced strong D 2 mRNA expression in PCC and for the first time in PGL. PCC/PGL express sst 2 mRNA at levels similar to those of GEP-NETs. New drugs can target ssts and D 2 more efficiently than current somatostatin analogs. Moreover, transporters like NAT and VMAT1/2, could be co-targeted with sst, as a basis of new radionuclide compounds in the imaging and treatment of these tumors.

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Section: Discussionmentioning

confidence: 98%

Expression of somatostatin receptors, dopamine D2 receptors, noradrenaline transporters, and vesicular monoamine transporters in 52 pheochromocytomas and paragangliomas

Saveanu¹,

Mureşan²,

Micco³

et al. 2011

Endocrine Related Cancer

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“…This increase occurs concurrent with a redistribution of VMAT-2 protein from the membrane-associated fraction to the cytoplasmic fraction. Both phenomena are DA receptor-mediated, and they could be manipulated pharmacologically, because in vivo pretreatment with either a D 1 or a D 2 receptor antagonist attenuates these changes, and a D 2 receptor agonist mimics the effects of MPD (Sandoval et al, 2002;Truong et al, 2004). The present study expands upon these findings by demonstrating that MPD treatment increases the density of kinetically active VMAT-2 in the cytoplasmic vesicle fraction without affecting either the catalytic rate constant (10 s Ϫ1 ) or the rate constant for DA binding to the VMAT-2 (ϳ3 ϫ 10 7 M Ϫ1 s Ϫ1 ).…”

Section: Discussionmentioning

confidence: 99%

Methylphenidate Administration Alters Vesicular Monoamine Transporter-2 Function in Cytoplasmic and Membrane-Associated Vesicles

Volz¹,

Farnsworth²,

King³

et al. 2007

J Pharmacol Exp Ther

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109

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In vivo methylphenidate (MPD) administration increases vesicular monoamine transporter-2 (VMAT-2) immunoreactivity, VMAT-2-mediated dopamine (DA) transport, and DA content in a nonmembrane-associated (referred to herein as cytoplasmic) vesicular subcellular fraction purified from rat striatum: a phenomenon attributed to a redistribution of VMAT-2-associated vesicles within nerve terminals. In contrast, the present study elucidated the nature of, and the impact of MPD on, VMAT-2-associated vesicles that cofractionate with synaptosomal membranes after osmotic lysis (referred to herein as membrane-associated vesicles). Results revealed that, in striking contrast to the cytoplasmic vesicles, DA transport velocity versus substrate concentration curves in the membrane-associated vesicles were sigmoidal, suggesting positive cooperativity with respect to DA transport. Additionally, DA transport into membrane-associated vesicles was greater in total capacity in the presence of high DA concentrations than transport into cytoplasmic vesicles. Of potential therapeutic relevance, MPD increased DA transport into the membrane-associated vesicles despite rapidly decreasing (presumably by redistributing) VMAT-2 immunoreactivity in this fraction. Functional relevance was suggested by findings that MPD treatment increased both the DA content of the membrane-associated vesicle fraction and K ϩ -stimulated DA release from striatal suspensions. In summary, the present data demonstrate the existence of a previously uncharacterized pool of membrane-associated VMAT-2-containing vesicles that displays novel transport kinetics, has a large sequestration capacity, and responds to in vivo pharmacological manipulation. These findings provide insight into both the regulation of vesicular DA sequestration and the mechanism of action of MPD, and they may have implications regarding treatment of disorders involving abnormal DA disposition, including Parkinson's disease and substance abuse.Methylphenidate (MPD) is a commonly prescribed psychostimulant used to treat attention-deficit hyperactivity disorder. It is well established that MPD binds with high affinity to the neuronal dopamine transporter (DAT) where it blocks the inward transport of dopamine (DA) (Wayment et al., 1999;. In addition, MPD indirectly affects DA transport by the vesicular monoamine transporter-2 (VMAT-2), a transporter protein that is responsible for the sequestration of cytoplasmic DA. Specifically, MPD administration increases [ 3 H]DA transport into nonmembrane-associated (referred to herein as cytoplasmic) vesicles purified from lysates of striatal synaptosomes prepared from treated rats (Sandoval et al., 2002(Sandoval et al., , 2003. MPD also increases DA content in the cytoplasmic vesicle subcellular fraction (Sandoval et al., 2002). These phenomena probably result from a redistribution of VMAT-2-containing vesicles within nerve terminals away from membranes and into the cytoplasm (Sandoval et al., 2002).Recent attention has focused on the regulation of cytop...

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“…Post-treatment with the DAT reuptake inhibitor amfonelic acid protects against METH-induced dopaminergic deficits as well (Marek et al, 1990). Of related interest are findings that administration of nonselective D 2 /D 3 receptor agonists increases VMAT2-mediated uptake, DHTBZ binding, and VMAT2 immunoreactivity (Brown et al, 2001a;Truong et al, 2003Truong et al, , 2004. Given the presumed role for decreased VMAT2 function in the dopaminergic deficits associated with PD (see discussion above), it has been suggested that treatment with reuptake inhibitors such as MPD or D 2 /D 3 agonists may slow the neurodegenerative processes associated with the disorder.…”

Section: B Pharmacological Manipulation Of Vesicular Monoamine Transmentioning

confidence: 99%

Regulation of the Dopamine and Vesicular Monoamine Transporters: Pharmacological Targets and Implications for Disease

et al. 2015

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Dopamine D2 receptor activation increases vesicular dopamine uptake and redistributes vesicular monoamine transporter-2 protein

Cited by 43 publications

References 27 publications

Expression of somatostatin receptors, dopamine D2 receptors, noradrenaline transporters, and vesicular monoamine transporters in 52 pheochromocytomas and paragangliomas

Expression of somatostatin receptors, dopamine D2 receptors, noradrenaline transporters, and vesicular monoamine transporters in 52 pheochromocytomas and paragangliomas

Methylphenidate Administration Alters Vesicular Monoamine Transporter-2 Function in Cytoplasmic and Membrane-Associated Vesicles

Regulation of the Dopamine and Vesicular Monoamine Transporters: Pharmacological Targets and Implications for Disease

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