Cytosolic Sulfotransferase 1A3 Is Induced by Dopamine and Protects Neuronal Cells from Dopamine Toxicity

Sidharthan, Neelima P.; Minchin, Rodney F.; Butcher, Neville J.

doi:10.1074/jbc.m113.493239

Cited by 30 publications

(35 citation statements)

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“…Activation of D 1 and NMDA receptors converge in the ERK1/2 MAP kinase cascade [33]. pERKs translocate to the Neural cell toxicity by dopamine is mediated by both cell surface receptors [34,35] and by intracellular metabolism leading to increased NAD(P) + /NAD(P)H ratios (Giménez-Xavier et al [36] and references therein, [37]). Toxic mechanisms include a dopamine-induced increase in cytosolic SULT1A1/3 sulfotransferase levels, the enzyme that metabolizes the neurotransmitter to dopaminesulfate.…”

Section: Discussionmentioning

confidence: 99%

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Heteroreceptor Complexes Formed by Dopamine D1, Histamine H3, and N-Methyl-D-Aspartate Glutamate Receptors as Targets to Prevent Neuronal Death in Alzheimer’s Disease

et al. 2016

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Alzheimer's disease (AD) is a neurodegenerative disorder causing progressive memory loss and cognitive dysfunction. Anti-AD strategies targeting cell receptors consider them as isolated units. However, many cell surface receptors cooperate and physically contact each other forming complexes having different biochemical properties than individual receptors. We here report the discovery of dopamine D, histamine H, and N-methyl-D-aspartate (NMDA) glutamate receptor heteromers in heterologous systems and in rodent brain cortex. Heteromers were detected by co-immunoprecipitation and in situ proximity ligation assays (PLA) in the rat cortex where H receptor agonists, via negative cross-talk, and H receptor antagonists, via cross-antagonism, decreased D receptor agonist signaling determined by ERK1/2 or Akt phosphorylation, and counteracted D receptor-mediated excitotoxic cell death. Both D and H receptor antagonists also counteracted NMDA toxicity suggesting a complex interaction between NMDA receptors and D-H receptor heteromer function. Likely due to heteromerization, H receptors act as allosteric regulator for D and NMDA receptors. By bioluminescence resonance energy transfer (BRET), we demonstrated that D or H receptors form heteromers with NR1A/NR2B NMDA receptor subunits. D-H-NMDA receptor complexes were confirmed by BRET combined with fluorescence complementation. The endogenous expression of complexes in mouse cortex was determined by PLA and similar expression was observed in wild-type and APP/PS1 mice. Consistent with allosteric receptor-receptor interactions within the complex, H receptor antagonists reduced NMDA or D receptor-mediated excitotoxic cell death in cortical organotypic cultures. Moreover, H receptor antagonists reverted the toxicity induced by ß-amyloid peptide. Thus, histamine H receptors in D-H-NMDA heteroreceptor complexes arise as promising targets to prevent neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

“…Induction of sulfotransferases is preceded by dopamine-receptor-mediated ERK phosphorylation and inhibited by the D 1 receptor antagonist SCH-23390. Interestingly, induction of SULT1A1/3 requires NMDA receptor signaling thus suggesting a dopamine D 1 -NMDA receptor-mediated mechanism [37].…”

Section: Discussionmentioning

confidence: 99%

Heteroreceptor Complexes Formed by Dopamine D1, Histamine H3, and N-Methyl-D-Aspartate Glutamate Receptors as Targets to Prevent Neuronal Death in Alzheimer’s Disease

et al. 2016

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“…Moreover, the effect of neurotransmitter (such as DA) on SULTs has been studied so limitedly. One recent paper demonstrated that SULT1A3 could be induced by DA in vitro, indicating the role of SULT1A3 in CNS by protecting neuronal cells from DA toxicity [25]. Besides, our previous results showed that methamphetamine, a structural analogue of DA, could induce the expressions of rSULT2A1 remarkably in rat liver and brain [23,24].…”

Section: Q2mentioning

confidence: 84%

Exogenous dopamine induces dehydroepiandrosterone sulfotransferase (rSULT2A1) in rat liver and changes the pharmacokinetic profile of moxifloxacin in rats

Shao

Wang

et al. 2015

Drug Metabolism and Pharmacokinetics

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“…To test the binding and specificity predictions of the docking studies and whether, like catechins, THB functions as an inhibitor, THB was tested in initial-rate studies as an inhibitor of SULT1A3 and the four other SULTs that, together with SULT1A3, constitute the major SULT isoforms found in human brain (29,30) and liver (1, 31) (i.e., SULTs 1A1, 1E1, 2A1, and 2B1b). The results ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…THB levels in normal-patient platelets are ∼200 nM (8.7 K i THB ) (36,37) and expected to decrease significantly upon cytokine stimulation (36). (iv) SULT1A3 is up-regulated in neurons in response to dopamine (30) and prevents toxicity by suppressing dopamine free-radical formation (38). Exogenous THB is known to induce apoptosis via free-radical mechanisms only in dopaminergic cell lines (39) and may do so by preventing dopamine sulfonation.…”

Section: Resultsmentioning

confidence: 99%

Tetrahydrobiopterin regulates monoamine neurotransmitter sulfonation

Cook

Wang

Leyh

2017

Proc. Natl. Acad. Sci. U.S.A.

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Monoamine neurotransmitters are among the hundreds of signaling small molecules whose target interactions are switched "on" and "off" via transfer of the sulfuryl-moiety (-SO 3 ) from PAPS (3′-phosphoadenosine 5′-phosphosulfate) to the hydroxyls and amines of their scaffolds. These transfer reactions are catalyzed by a small family of broad-specificity enzymes-the human cytosolic sulfotransferases (SULTs). The first structure of a SULT allosteric-binding site (that of SULT1A1) has recently come to light. The site is conserved among SULT1 family members and is promiscuous-it binds catechins, a naturally occurring family of flavanols. Here, the catechin-binding site of SULT1A3, which sulfonates monoamine neurotransmitters, is modeled on that of 1A1 and used to screen in silico for endogenous metabolite 1A3 allosteres. Screening predicted a single high-affinity allostere, tetrahydrobiopterin (THB), an essential cofactor in monoamine neurotransmitter biosynthesis. THB is shown to bind and inhibit SULT1A3 with high affinity, 23 (±2) nM, and to bind weakly, if at all, to the four other major SULTs found in brain and liver. The structure of the THB-bound binding site is determined and confirms that THB binds the catechin site. A structural comparison of SULT1A3 with SULT1A1 (its immediate evolutionary progenitor) reveals how SULT1A3 acquired high affinity for THB and that the majority of residue changes needed to transform 1A1 into 1A3 are clustered at the allosteric and active sites. Finally, sequence records reveal that the coevolution of these sites played an essential role in the evolution of simian neurotransmitter metabolism.sulfotransferase | tetrahydrobiopterin | neurotransmitter | allostery | evolution H uman cytosolic sulfotransferases (SULTs) regulate the activities of thousands of endogenous small-molecule metabolites and xenobiotics via transfer of the sulfuryl-moiety (-SO 3 ) to and from the hydroxyl-and amine-moieties of these acceptors. The 13 full-length SULT isoforms encoded in the human genome are expressed in tissue-and developmentally specific patterns (1-3). SULT substrate specificities are typically broad, overlapping, and centered on different areas of metabolism. The diversity of function across SULT isoforms results in a remarkably broad range of metabolic functions including potent regulation of steroids (4), thyroid (5) and peptide hormones (6), oxysterols (7), pheromones (8), selectins (9), and neurotransmitters (10, 11).Although recent work has deepened our understanding of SULT small-molecule allosteric regulation, the topic remains largely unexplored (12-16). The catechin-binding site is the most well-characterized SULT allosteric site (12). Catechins, a complex biomorphic family of SULT allosteric inhibitors, are found at high levels in tea leaves, cocoa, and coffee (17-19). The binding site is promiscuous in that it binds numerous catechins (15, 20) and related structures. The structure of the SULT1A1 catechin-binding site, the only published SULT allosteric-site structure, has recentl...

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Cytosolic Sulfotransferase 1A3 Is Induced by Dopamine and Protects Neuronal Cells from Dopamine Toxicity

Cited by 30 publications

References 50 publications

Heteroreceptor Complexes Formed by Dopamine D1, Histamine H3, and N-Methyl-D-Aspartate Glutamate Receptors as Targets to Prevent Neuronal Death in Alzheimer’s Disease

Heteroreceptor Complexes Formed by Dopamine D1, Histamine H3, and N-Methyl-D-Aspartate Glutamate Receptors as Targets to Prevent Neuronal Death in Alzheimer’s Disease

Exogenous dopamine induces dehydroepiandrosterone sulfotransferase (rSULT2A1) in rat liver and changes the pharmacokinetic profile of moxifloxacin in rats

Tetrahydrobiopterin regulates monoamine neurotransmitter sulfonation

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