Enhanced norepinephrine output during long-term desipramine treatment: A possible role for the extraneuronal monoamine transporter (SLC22A3)

Mooney, John J.; Samson, Jacky; Hennen, John; Pappalardo, Kathleen M.; McHale, Nancy L; Alpert, Jonathan E.; Koutsos, Martha; Schildkraut, Joseph J.

doi:10.1016/j.jpsychires.2007.07.009

Cited by 21 publications

(9 citation statements)

References 47 publications

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“…OCT3 is a low-affinity, high-capacity uptake transporter, formally known as extraneuronal monoamine transporter and also termed as the uptake-2 system, and is broadly expressed in non-neuronal cells (51). OCT3 expression on PVAT adipocytes has not yet been investigated.…”

Section: Discussionmentioning

confidence: 99%

Organic cation transporter 3 contributes to norepinephrine uptake into perivascular adipose tissue

Ayala‐Lopez

Jackson

Burnett

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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Watts SW. Organic cation transporter 3 contributes to norepinephrine uptake into perivascular adipose tissue. Am J Physiol Heart Circ Physiol 309: H1904 -H1914, 2015. First published October 2, 2015; doi:10.1152/ajpheart.00308.2015.-Perivascular adipose tissue (PVAT) reduces vasoconstriction to norepinephrine (NE). A mechanism by which PVAT could function to reduce vascular contraction is by decreasing the amount of NE to which the vessel is exposed. PVATs from male Sprague-Dawley rats were used to test the hypothesis that PVAT has a NE uptake mechanism. NE was detected by HPLC in mesenteric PVAT and isolated adipocytes. Uptake of NE (10 M) in mesenteric PVAT was reduced by the NE transporter (NET) inhibitor nisoxetine (1 M, 73.68 Ϯ 7.62%, all values reported as percentages of vehicle), the 5-hydroxytryptamine transporter (SERT) inhibitor citalopram (100 nM) with the organic cation transporter 3 (OCT3) inhibitor corticosterone (100 M, 56.18 Ϯ 5.21%), and the NET inhibitor desipramine (10 M) with corticosterone (100 M, 61.18 Ϯ 6.82%). Aortic PVAT NE uptake was reduced by corticosterone (100 M, 53.01 Ϯ 10.96%). Confocal imaging of mesenteric PVAT stained with 4-[4-(dimethylamino)-styrl]-N-methylpyridinium iodide (ASP ϩ ), a fluorescent substrate of cationic transporters, detected ASP ϩ uptake into adipocytes. ASP ϩ (2 M) uptake was reduced by citalopram (100 nM, 66.68 Ϯ 6.43%), corticosterone (100 M, 43.49 Ϯ 10.17%), nisoxetine (100 nM, 84.12 Ϯ 4.24%), citalopram with corticosterone (100 nM and 100 M, respectively, 35.75 Ϯ 4.21%), and desipramine with corticosterone (10 and 100 M, respectively, 50.47 Ϯ 5.78%). NET protein was not detected in mesenteric PVAT adipocytes. Expression of Slc22a3 (OCT3 gene) mRNA and protein in PVAT adipocytes was detected by RT-PCR and immunocytochemistry, respectively. These end points support the presence of a transporter-mediated NE uptake system within PVAT with a potential mediator being OCT3. PERIVASCULAR ADIPOSE TISSUE (PVAT) closely envelops many blood vessels of the body (65). This relationship between PVAT and the blood vessel has earned PVAT its place as the fourth layer of the blood vessel, the "tunica adiposa" (14). Beyond providing structural support, PVAT has many roles in modulating blood vessel function (68). The release of vasoactive molecules from PVAT influences vascular function by altering the proliferation, migration, inflammation, and contraction of vascular smooth muscle (9, 20 -22, 24, 46, 68, 72). Interestingly, a releasable pool of catecholamines is present in PVAT (5, 67). Although both contractile and anticontractile substances can be released from PVAT (9,22,24,25,72), the presence of PVAT on blood vessels generally reduces vessel contraction in response to various agonists, including norepinephrine (NE) (64). Knowledge on how these mechanisms interact to influence the anticontractile properties of PVAT in NE-induced contraction is not complete (36).The anticontractile effect of PVAT is lost in obesity and hypertension, implicating PVAT as an integral lin...

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Section: Discussionmentioning

confidence: 99%

Organic cation transporter 3 contributes to norepinephrine uptake into perivascular adipose tissue

Ayala‐Lopez

Jackson

Burnett

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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“…Only PAX3 plays a role in this function in deciduous PDL tissues, but in permanent PDL tissues, eight genes were identified: FOS , V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog ( KIT ), neural cell adhesion molecule 2 ( NCAM2 ), MYH10 , synaptotagmin I ( SYT1 ), solute carrier family 22, member 3 ( SLC22A3 ), cytochrome P450, family 1, subfamily B, polypeptide 1 ( CYP1B1 ), and jun proto-oncogene ( JUN ). Among these genes, FOS is known to be an indirect marker of neuronal activity because it is often expressed when neurons fire action potentials [65], NCAM2 is a type I membrane protein and is thought to induce neurite outgrowth [66], [67], SYT1 functions as a calcium regulator of neurotransmitter release [68], and SLC22A3 is an extraneuronal monoamine transporter and is involved in neurotransmission [69]. Furthermore, among the genes that are relatively strongly expressed in permanent PDL tissues, dedicator of cytokinesis 3 ( DOCK3 ), LRRTM1 , leucine-rich repeat transmembrane neuronal 3 ( LRRTM3 ), protease, serine 12 ( PRSS12 ), and cAMP-regulated phosphoprotein, 21 kDa ( ARPP21 ) are genes known to be associated with neuronal signaling systems.…”

Section: Discussionmentioning

confidence: 99%

Comparative Gene Expression Analysis of the Human Periodontal Ligament in Deciduous and Permanent Teeth

et al. 2013

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There are histological and functional differences between human deciduous and permanent periodontal ligament (PDL) tissues. The aim of this study was to determine the differences between these two types of tissue at the molecular level by comparing their gene expression patterns. PDL samples were obtained from permanent premolars (n = 38) and anterior deciduous teeth (n = 31) extracted from 40 healthy persons. Comparative cDNA microarray analysis revealed several differences in gene expression between the deciduous and permanent PDL tissues. These findings were verified by qRT-PCR (quantitative reverse-transcription–polymerase chain reaction) analysis, and the areas where genes are expressed were revealed by immunohistochemical staining. The expressions of 21 genes were up-regulated in deciduous relative to PDL tissues, and those of 30 genes were up-regulated in permanent relative to deciduous PDL tissues. The genes that were up-regulated in deciduous PDL tissues were those involved in the formation of the extracellular matrix (LAMC2, LAMB3, and COMP), tissue development (IGF2BP, MAB21L2, and PAX3), and inflammatory or immune reactions leading to tissue degradation (IL1A, CCL21, and CCL18). The up-regulated genes in permanent PDL tissues were related to tissue degradation (IL6 and ADAMTS18), myocontraction (PDE3B, CASQ2, and MYH10), and neurological responses (FOS, NCAM2, SYT1, SLC22A3, DOCK3, LRRTM1, LRRTM3, PRSS12, and ARPP21). The analysis of differential gene expressions between deciduous and permanent PDL tissues aids our understanding of histological and functional differences between them at the molecular level.

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“…Schildkraut and Mooney (2004) proposed the hypothesis that drugs that increase normetanephrine, or that block the extraneuronal transporter (uptake 2), will reduce the latency to clinical efficacy of antidepressants, such as desipramine, which block NE uptake. While evidence supporting this hypothesis is growing (Mooney et al, 2008), debate continues regarding the identity of “uptake 2”. Some schools of thought believe “uptake 2” is the organic cation transporter (OCT), specifically the OCT3 subtype, while others dispute this idea.…”

Section: Old Ideas New Discoveriesmentioning

confidence: 99%

Unfaithful neurotransmitter transporters: Focus on serotonin uptake and implications for antidepressant efficacy

Daws

2009

Pharmacology & Therapeutics

195

203

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Biogenic amine transporters for serotonin, norepinephrine and dopamine (SERT, NET and DAT respectively), are the key players terminating transmission of these amines in the central nervous system by their high-affinity uptake. They are also major targets for many antidepressant drugs. Interestingly however, drugs targeted to a specific transporter do not appear to be as clinically efficacious as those that block two or all three of these transporters. A growing body of literature, reviewed here, supports the idea that promiscuity among these transporters (the uptake of multiple amines in addition to their “native” transmitter) may account for improved therapeutic effects of dual and triple uptake blockers. However, even these drugs do not provide effective treatment outcomes for all individuals. An emerging literature suggests that “non-traditional” transporters such as organic cation transporters (OCT) and the plasma membrane monoamine transporter (PMAT) may contribute to the less than hoped for efficacy of currently prescribed uptake inhibitors. OCT and PMAT are capable of clearing biogenic amines from extracellular fluid and may serve to buffer the effects of frontline antidepressants, such as selective serotonin reuptake inhibitors. In addition, polymorphisms that occur in the genes encoding the transporters can lead to variation in transporter expression and function (e.g. the serotonin transporter linked polymorphic region; 5-HTTLPR) and can have profound effects on treatment outcome. This may be accounted for, in part, by compensatory adaptations in other transporters. This review synthesizes the existing literature, focusing on serotonin to illustrate and revive a model for the rationale design of improved antidepressants.

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Enhanced norepinephrine output during long-term desipramine treatment: A possible role for the extraneuronal monoamine transporter (SLC22A3)

Cited by 21 publications

References 47 publications

Organic cation transporter 3 contributes to norepinephrine uptake into perivascular adipose tissue

Organic cation transporter 3 contributes to norepinephrine uptake into perivascular adipose tissue

Comparative Gene Expression Analysis of the Human Periodontal Ligament in Deciduous and Permanent Teeth

Unfaithful neurotransmitter transporters: Focus on serotonin uptake and implications for antidepressant efficacy

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