Regulation of serotonin transporter activity by adenosine in intestinal epithelial cells

Matheus, Nyurky; Mendoza, Carmen; Iceta, Ruth; Mesonero, José E.; Alcalde, Ana Isabel

doi:10.1016/j.bcp.2009.06.006

Cited by 16 publications

(15 citation statements)

References 37 publications

(54 reference statements)

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“…127 Hypoxia induces 5-HT synthesis and secretion from EC cells. Adenosine acts to decrease serotonin transporter (SERT) activity 128 that would serve to increase 5-HT signaling in the gut. Activation of A 2B AR via MAPK/CREB and TPH-1 signaling amplifies the effect of hypoxia in human EC cells.…”

Section: 0 Adenosinergic Drugsmentioning

confidence: 99%

Potential for Developing Purinergic Drugs for Gastrointestinal Diseases

Ochoa-Cortés¹,

Liñán-Rico²,

Jacobson³

et al. 2014

Inflammatory Bowel Diseases

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Treatments for IBD, IBS, FD or motility disorders are not adequate, and purinergic drugs offer exciting new possibilities. GI symptoms that could be targeted for therapy include visceral pain, inflammatory pain, dysmotility, constipation and diarrhea. The focus of this review is on potential for developing purinergic drugs for clinical trials to treat GI symptoms. Purinergic receptors are divided into adenosine P1 (A1,A2A,A2B,A3), ionotropic ATP-gated P2X ion channel (P2X1–7) or metabotropic P2Y1,2,4,6,11–14 receptors. There is good experimental evidence for targeting A2A, A2B, A3, P2X7, P2X3 receptors or increasing endogenous adenosine levels to treat IBD, inflammatory pain, IBS/visceral pain, inflammatory-diarrhea and motility disorders. Purine genes are also potential biomarkers of disease. Advances in medicinal-chemistry have an accelerated pace toward clinical trials: Methotrexate and sulfasalazine, used to treat IBD, act by stimulating CD73-dependent adenosine production. ATP protects against NSAID-induced enteropathy and has pain-relieving properties in humans. A P2X7R antagonist AZD9056 is in clinical trials for CD. A3 AR drugs target inflammatory diseases (e.g. CF101; CF102). Dipyridamole, a nucleoside uptake-inhibitor, is in trials for endotoxemia. Drugs for pain in clinical-trials include P2X3/P2X2/3(AF-219) and P2X7(GSK1482160) antagonists and A1(GW493838) or A2A(BVT.115959) agonists. IberogastR is a phytopharmacon targeting purine-mechanisms with efficacy in IBS and FD. Purinergic drugs have excellent safety/efficacy profile for prospective clinical trials in IBD, IBS, FD and inflammatory-diarrhea. Genetic polymorphisms and caffeine consumption may affect susceptibility to treatment. Further studies in animals can clarify mechanisms and test new-generation drugs. Finally, there is still a huge gap in our knowledge of human pathophysiology of purinergic signaling.

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Section: 0 Adenosinergic Drugsmentioning

confidence: 99%

Potential for Developing Purinergic Drugs for Gastrointestinal Diseases

Ochoa-Cortés¹,

Liñán-Rico²,

Jacobson³

et al. 2014

Inflammatory Bowel Diseases

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“…Receptor-mediated regulation of SERT has also been documented. Activation of ARs (adenosine receptors), 5-HT 1B , atypical histamine receptors and BDNF (brain-derived neurotrophic factor)/TrkB (tropomyosin kinase B) stimulates SERT activity [22][23][24][25][26][27], whereas stimulation of α 2 -adrenergic receptor signalling cascades reduces 5-HT uptake [28]. In addition, SERT substrates and inhibitors can also influence kinase/phosphatase-mediated SERT regulation [29].…”

Section: Introductionmentioning

confidence: 99%

Akt-mediated regulation of antidepressant-sensitive serotonin transporter function, cell-surface expression and phosphorylation

Rajamanickam

Annamalai

Rahbek-Clemmensen

et al. 2015

Biochemical Journal

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The serotonin [5-HT (5-hydroxytryptamine)] transporter (SERT) controls serotonergic neurotransmission in the brain by rapid clearance of 5-HT from the synaptic cleft into presynaptic neurons. SERTs are primary targets for antidepressants for therapeutic intervention of mood disorders. Our previous studies have identified the involvement of several signalling pathways and protein kinases in regulating SERT function, trafficking and phosphorylation. However, whether Akt/PKB (protein kinase) regulates SERT function is not known. In the present study, we made the novel observation that inhibition of Akt resulted in the down-regulation of SERT function through the regulation of SERT trafficking and phosphorylation. Akt inhibitor Akt X {10-(4'-[N-diethylamino)butyl]-2-chlorophenoxazine} reduced the endogenously phosphorylated Akt and significantly decreased 5-HT uptake and 5-HT-uptake capacity. Furthermore, SERT activity is also reduced by siRNA down-regulation of total and phospho-Akt levels. The reduction in SERT activity is paralleled by lower levels of cell-surface SERT protein, reduced SERT exocytosis with no effect on SERT endocytosis and accumulation of SERT in intracellular endocytic compartments with the most prominent localization to late endosomes and lysosomes. Akt2 inhibitor was more effective than Akt1 inhibitor in inhibiting SERT activity. Inhibition of downstream Akt kinase GSK3α/β (glycogen synthase kinase α/β) stimulates SERT function. Akt inhibition leads to a decrease in SERT basal phosphorylation. Our results provide evidence that Akt regulates SERT function and cell-surface expression by regulating the intracellular SERT distribution and plasma membrane availability, which perhaps may be linked to SERT phosphorylation state. Thus any changes in the activation of Akt and/or GSK3α/β could alter SERT-mediated 5-HT clearance and subsequently serotonergic neurotransmission.

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“…Thus, some of these molecules at high concentrations may act as proinflammatory factors. This is the case for serotonin (5-HT) [7, 8], adenosine [9, 10], and TNF α [11], whereas others, such as melatonin, may act either as a proinflammatory factor at high concentrations or as an anti-inflammatory molecule depending on the cell conditions [12]. Moreover, interleukin-10 (IL-10), a well-known anti-inflammatory cytokine [13–15], has also been shown to modulate intestinal physiology [16].…”

Section: Introductionmentioning

confidence: 99%

IL-10 Counteracts Proinflammatory Mediator Evoked Oxidative Stress in Caco-2 Cells

Latorre

Matheus

Layunta

et al. 2014

Mediators of Inflammation

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Oxidative stress is thought to play a key role in the development of intestinal damage in intestinal inflammatory diseases. Several molecules are involved in the intestinal inflammation, either as pro- or anti-inflammatory factors; however, their effects on intestinal oxidative stress seem to be controversial. This work analyzes the contribution of pro- and anti-inflammatory molecules to the balance of oxidative damage in intestinal epithelial cells, as well as their effects on cellular antioxidant enzyme activity. With this purpose, the lipid and protein oxidation, together with the activity of catalase, superoxide dismutase, and glutathione peroxidase, were determined in the Caco-2 cells treated with serotonin, adenosine, melatonin, and TNFα, as proinflammatory factors, and IL-10, as an anti-inflammatory cytokine. The results have shown that all the proinflammatory factors assayed increased oxidative damage. In addition, these factors also inhibited the activity of antioxidant enzymes in the cells, except melatonin. In contrast, IL-10 did not alter these parameters but was able to reduce the prooxidant effects yielded by serotonin, adenosine, melatonin, or TNFα, in part by restoring the antioxidant enzymes activities. In summary, proinflammatory factors may induce oxidative damage in intestinal epithelial cells, whereas IL-10 seems to be able to restore the altered redox equilibrium in Caco-2 cells.

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Regulation of serotonin transporter activity by adenosine in intestinal epithelial cells

Cited by 16 publications

References 37 publications

Potential for Developing Purinergic Drugs for Gastrointestinal Diseases

Potential for Developing Purinergic Drugs for Gastrointestinal Diseases

Akt-mediated regulation of antidepressant-sensitive serotonin transporter function, cell-surface expression and phosphorylation

IL-10 Counteracts Proinflammatory Mediator Evoked Oxidative Stress in Caco-2 Cells

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