Involvement of Organic Cation Transporter-3 and Plasma Membrane Monoamine Transporter in Serotonin Uptake in Human Brain Vascular Smooth Muscle Cells

Li, Rachel Wai-sum; Yang, Cui; Kwan, Yiu Wa; Chan, Shun‐Wan; Lee, Simon Ming‐Yuen; Leung, George Pak-Heng

doi:10.3389/fphar.2013.00014

Cited by 14 publications

(13 citation statements)

References 54 publications

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“…It is likely that the uptake of metformin, which is positively charged at physiological pH, is mediated by the organic cation transporter-3 (OCT-3). In this regard, recent studies demonstrate high expression levels of OCT-3 in vascular smooth muscle and skeletal muscle [42, 49], in comparison with the predominant OCT-1 and OCT-2 isoforms that mediate metformin uptake in the liver and kidney, respectively. Thus, after uptake through distinct transporters in vascular smooth muscle cells, 2-deoxyglucose, AICAR, and metformin would utilize different mechanisms to activate AMPK.…”

Section: Discussionmentioning

confidence: 99%

Metformin exaggerates phenylephrine-induced AMPK phosphorylation independent of CaMKKβ and attenuates contractile response in endothelium-denuded rat aorta

Pyla¹,

Osman²,

Pichavaram³

et al. 2014

Biochemical Pharmacology

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Metformin, a widely prescribed antidiabetic drug, has been shown to reduce the risk of cardiovascular disease, including hypertension. Its beneficial effect toward improved vasodilation results from its ability to activate AMPK and enhance nitric oxide formation in the endothelium. To date, metformin regulation of AMPK has not been fully studied in intact arterial smooth muscle, especially during contraction evoked by G protein-coupled receptor (GPCR) agonists. In the present study, ex vivo incubation of endothelium-denuded rat aortic rings with 3 mM metformin for 2 hours resulted in significant accumulation of metformin (~600 pmoles/mg tissue), as revealed by LC-MS/MS MRM analysis. However, metformin did not show significant increase in AMPK phosphorylation under these conditions. Exposure of aortic rings to a GPCR agonist (e.g., phenylephrine) resulted in enhanced AMPK phosphorylation by ~2.5-fold. Importantly, in metformin-treated aortic rings, phenylephrine challenge showed an exaggerated increase in AMPK phosphorylation by ~9.7-fold, which was associated with an increase in AMP/ATP ratio. Pretreatment with compound C (AMPK inhibitor) prevented AMPK phosphorylation induced by phenylephrine alone and also that induced by phenylephrine after metformin treatment. However, pretreatment with STO-609 (CaMKKβ inhibitor) diminished AMPK phosphorylation induced by phenylephrine alone but not that induced by phenylephrine after metformin treatment. Furthermore, attenuation of phenylephrine-induced contraction (observed after metformin treatment) was prevented by AMPK inhibition but not by CaMKKβ inhibition. Together, these findings suggest that, upon endothelial damage in the vessel wall, metformin uptake by the underlying vascular smooth muscle would accentuate AMPK phosphorylation by GPCR agonists independent of CaMKKβ to promote vasorelaxation.

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Section: Discussionmentioning

confidence: 99%

Metformin exaggerates phenylephrine-induced AMPK phosphorylation independent of CaMKKβ and attenuates contractile response in endothelium-denuded rat aorta

Pyla¹,

Osman²,

Pichavaram³

et al. 2014

Biochemical Pharmacology

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“…The transporter is expressed in neurons (Cui et al, 2009;Graf et al, 2013;Hill and Gasser, 2013;Shang et al, 2003;Vialou et al, 2004), including dopamine neurons (Mayer et al, 2018), and glial cells, including astrocytes (Cui et al, 2009;Takeda et al, 2002) and microglia (He et al, 2017). It is also expressed in oligodendrocytes (Gasser et al, 2009), ependymal cells (Gasser et al, 2006;Gasser et al, 2009), and vascular endothelial cells in the brain (Li et al, 2013). The broad expression of this high-capacity monoamine transporter suggests that it plays an essential role in the regulation of extracellular monoamine concentrations in a variety of microenvironments.…”

Section: Cellular and Subcellular Localization Of Oct3mentioning

confidence: 99%

Roles for the uptake2 transporter OCT3 in regulation of dopaminergic neurotransmission and behavior

Gasser

2019

Neurochemistry International

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Transporter-mediated uptake determines the peak concentration, duration, and physical spread of released monoamines. Most studies of monoamine clearance focus on the presynaptic uptake transporters SERT, NET and DAT. However, recent studies have demonstrated the expression of the uptake transporter OCT3 (organic cation transporter 3), throughout the rodent brain. In contrast to NET, DAT and SERT, OCT3 has higher capacity and lower affinity for substrates, is sodium-independent, and is multi-specific, with the capacity to transport norepinephrine, dopamine, serotonin and histamine. OCT3 is insensitive to inhibition by cocaine and antidepressant drugs but is inhibited directly by the glucocorticoid hormone corticosterone. Thus, OCT3 represents a novel, stress hormone-sensitive, monoamine transport mechanism. Incorporating this transporter into current models of monoaminergic neurotransmission requires information on: A) the cellular and subcellular localization of the transporter; B) the effects of OCT3 inhibitors on monoamine clearance; and C) the consequences of decreased OCT3-mediated transport on physiology and/or behavior. This review summarizes studies describing the anatomical distribution of OCT3, its cellular and subcellular localization, its contribution to the regulation of dopaminergic signaling, and its roles in the regulation of behavior. Together, these and other studies suggest that both Uptake and Uptake transporters play key roles in regulating monoaminergic neurotransmission and the effects of monoamines on behavior.

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“…Studies examining the cellular and subcellular distributions of OCT3 suggest that this transporter plays a variety of roles in regulating monoaminergic neurotransmission. Expression of OCT3 has been demonstrated in neurons (Cui et al, 2009;Gasser et al, 2009;Hill et al, 2011;Shang et al, 2003;Vialou et al, 2004), astrocytes (Cui et al, 2009;Gasser et al, 2017;Takeda et al, 2002), microglia (He et al, 2017), oligodendrocytes (Gasser et al, 2009), ependymal (Gasser et al, 2006;Gasser et al, 2009) and vascular endothelial cells (Li et al, 2013) in the brain. Thus, OCT3 is positioned to regulate extracellular monoamine concentrations in a variety of microenvironments in the central nervous system.…”

Section: Distribution Of Oct3 In Rat Brainmentioning

confidence: 99%

Organic cation transporter 3: A cellular mechanism underlying rapid, non-genomic glucocorticoid regulation of monoaminergic neurotransmission, physiology, and behavior

Gasser

Lowry

2018

Hormones and Behavior

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Contribution to Special Issue on Fast effects of steroids. Corticosteroid hormones act at intracellular glucocorticoid receptors (GR) and mineralocorticoid receptors (MR) to alter gene expression, leading to diverse physiological and behavioral responses. In addition to these classical genomic effects, corticosteroid hormones also exert rapid actions on physiology and behavior through a variety of non-genomic mechanisms, some of which involve GR or MR, and others of which are independent of these receptors. One such GR-independent mechanism involves corticosteroid-induced inhibition of monoamine transport mediated by "uptake" transporters, including organic cation transporter 3 (OCT3), a low-affinity, high-capacity transporter for norepinephrine, epinephrine, dopamine, serotonin and histamine. Corticosterone directly and acutely inhibits OCT3-mediated transport. This review describes the studies that initially characterized uptake processes in peripheral tissues, and outlines studies that demonstrated OCT3 expression and corticosterone-sensitive monoamine transport in the brain. Evidence is presented supporting the hypothesis that corticosterone can exert rapid, GR-independent actions on neuronal physiology and behavior by inhibiting OCT3-mediated monoamine clearance. Implications of this mechanism for glucocorticoid-monoamine interactions in the context-dependent regulation of behavior are discussed.

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Involvement of Organic Cation Transporter-3 and Plasma Membrane Monoamine Transporter in Serotonin Uptake in Human Brain Vascular Smooth Muscle Cells

Cited by 14 publications

References 54 publications

Metformin exaggerates phenylephrine-induced AMPK phosphorylation independent of CaMKKβ and attenuates contractile response in endothelium-denuded rat aorta

Metformin exaggerates phenylephrine-induced AMPK phosphorylation independent of CaMKKβ and attenuates contractile response in endothelium-denuded rat aorta

Roles for the uptake2 transporter OCT3 in regulation of dopaminergic neurotransmission and behavior

Organic cation transporter 3: A cellular mechanism underlying rapid, non-genomic glucocorticoid regulation of monoaminergic neurotransmission, physiology, and behavior

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