Fwd: Sulfur's relationships to NMDA

[Guest guest]

,

This article below is suggesting some sulfurish issues that may account for

alternative reactions at glutamate receptors. I don't know if this has to

do with the sort of reactions you have heard described with MSG and maybe

some related compounds.

I apologize to listmates for the technicality here. Don't worry if your

eyes gloss over and you don't read to deep into this....The main point I'm

making is that some models are just way too simplistic! Sometimes the

best way to correct an adverse reaction to something is to work on some

related chemistry, a principle that certainly applies to a lot of things on

this list....

>Date: Thu, 17 Mar 2005 01:54:22 -0600

>Subject: Sulfur's relationships to NMDA

>

>Listmates,

>

>The chemical NMDA is a glutamate analog that specifically imitates the

>activity of the physiological amino acids glutamate or aspartate with a

>cosignal from glycine, allowing for the flow of sodium or calcium into the

>cell. It seems reasonable to suspect that not only does this input of

>cations accomplish a depolarisation of the plasma membrane and the

>generation of an electrical current (and similar changes on

>NMDA-containing non-neuronal cells like lymphocytes and osteoclasts), but

>the NMDA receptor may also be giving information to the cell about the

>outside quantities of things that go into making glutathione and

>regulating cystine's crossing of membranes. I've put some studies below to

>get us thinking in sulfurish directions about NMDA...this is only a beginning.

>

>We cannot forget, when thinking about receptors responsive to glutamate,

>that there may very well be on the same cell a host of glutamate/cystine

>exchangers which at some points can be very important for getting cystine

>into the cell in exchange for intracellular glutamate. Of couse, the

>exchanger may work in the other direction when extracellular glutamate is

>high...which would be expected to happen at the same time that glutamate

>receptors like the NMDA would be getting information about the enhanced

>quantity of glutamate outside the cell.

>

>I've also put below a series of studies showing some sulfurish territory

>in what kynurenine is doing as an antagonist for glutamatergic receptors:

>not only the ionotropic glutamate receptors NMDA and AMPA, but also the

>metabotropic glutamate receptors as well. How is this " global " antagonism

>for glutamate receptors important? As you read the abstract, you will

>notice a familiar cast of characters, like homocysteine, SAH, methionine

>and cysteine. Important to note is that at a low level, homocysteine

>enhanced the production of kynurenic acid, but at a higher level, it

>inhibited it. B6 deficiency, which changes a lot of things about how the

>sulfur chemistry works, reduced the amount of kynurenic acid that showed

>up in urine in rats, while at the same time, xanthurenic acid increased

>drastically. Xanthurenic acid has no similar effect on excitatory amino

>acid receptors like the NMDA. How does all this work together, and how

>does it work in children with methylation and sulfur problems?

>

>The ratio between SAH and homocysteine is an important regulator in the

>shared cycle of remethylation with its branch to transsulfuration. In

>this other context, SAH was a more potent regulator than homocysteine to

>the production of the NMDA antagonist kynurenic acid. Because of an

>association of sulfur issues and tryptophan issues in a lot of

>neurological conditions, this could be a place to suspect a deliberate

>interaction between the sulfur chemistry and the tryptophan chemistry.

>

>Enjoy the reading!

>

>

>

>

>14: J Neurochem. 1999 Oct;73(4):1566-72.

>

>Glutathione efflux induced by NMDA and kainate: implications in neurotoxicity?

>

>Wallin C, Weber SG, Sandberg M.

>

>Department of Anatomy and Cell Biology, University of Goteborg, Sweden.

>

>Neurotoxicity in acute as well as chronic neurological diseases may be partly

>mediated by oxidative stress caused by overactivation of glutamate

>receptors. A

>key component of the cellular defense against oxidative stress is reduced

>glutathione. In our earlier work, we have shown that ischemia in brain induces

>increased efflux, elevated metabolism, and decreased tissue concentrations of

>glutathione. In this study, we have evaluated the effect of glutamate receptor

>activation on the efflux of glutathione from hippocampus in vitro. NMDA and

>kainate induced a delayed increase in glutathione, taurine, and

>phosphoethanolamine efflux. Extracellular glutathione was recovered mainly in

>the reduced form (85-95%); the efflux was dependent on extracellular

>calcium but

>unrelated to dantrolene-sensitive intracellular calcium release and

>independent

>of glutathione or NO synthesis. The NMDA-induced efflux of glutathione was

>enhanced by blockage of gamma-glutamyl transpeptidase, indicating an increased

>transpeptidation of glutathione after NMDA receptor activation. Our results

>suggest that increased efflux of glutathione could be a factor in initiating

>nerve cell death via a change in intracellular redox potential and/or a

>decrease

>in the intracellular capacity for inactivation of reactive oxygen species.

>

>PMID: 10501202 [PubMed - indexed for MEDLINE]

>

> Nutr Rev. 2004 Sep;62(9):348-53. Related Articles, Links

> Click here to read

> New roles for cysteine and transsulfuration enzymes: production of

> H2S, a neuromodulator and smooth muscle relaxant.

>

> Dominy JE, Stipanuk MH.

>

> Division of Nutritional Sciences, Cornell University, Ithaca, NY

> 14853, USA.

>

> The enzymes of the transsulfuration pathway also have the capacity to

> catalyze the desulfhydration of cysteine. Recent studies demonstrate a

> role of the transsulfuration enzymes, cystathionine gamma-lyase and

> cystathionine beta-synthase, in catalyzing the desulfhydration of

> cysteine in brain and smooth muscle. The H2S produced from cysteine

> functions as a neuromodulator and smooth muscle relaxant. In

> glutamatergic neurons, the production of H2S by cystathionine

> beta-synthase enhances N-methyl-D-aspartate (NMDA) receptor-mediated

> currents. In smooth muscle cells, H2S produced by cystathionine

> gamma-lyase enhances the outward flux of potassium by opening potassium

> channels, leading to hyperpolarization of membrane potential and smooth

> muscle relaxation.

>

> Publication Types:

>

> * Review

> * Review, Tutorial

>

>

> PMID: 15497768 [PubMed - indexed for MEDLINE]

>

>Trends Neurosci. 2002 Sep;25(9):474-80. Related Articles, Links

> Click here to read

> Cysteine regulation of protein function--as exemplified by

> NMDA-receptor modulation.

>

> Lipton SA, Choi YB, Takahashi H, Zhang D, Li W, Godzik A, Bankston LA.

>

> Center for Neuroscience and Aging, The Burnham Institute, 10901 North

> Torrey Pines Road, La Jolla, CA 92037, USA. slipton@...

>

> Until recently cysteine residues, especially those located

> extracellularly, were thought to be important for metal coordination,

> catalysis and protein structure by forming disulfide bonds - but they

> were not thought to regulate protein function. However, this is not the

> case. Crucial cysteine residues can be involved in modulation of protein

> activity and signaling events via other reactions of their thiol

> (sulfhydryl; -SH) groups. These reactions can take several forms, such as

> redox events (chemical reduction or oxidation), chelation of transition

> metals (chiefly Zn(2+), Mn(2+) and Cu(2+)) or S-nitrosylation [the

> catalyzed transfer of a nitric oxide (NO) group to a thiol group]. In

> several cases, these disparate reactions can compete with one another for

> the same thiol group on a single cysteine residue, forming a molecular

> switch composed of a latticework of possible redox, NO or Zn(2+)

> modifications to control protein function. Thiol-mediated regulation of

> protein function can also involve reactions of cysteine residues that

> affect ligand binding allosterically. This article reviews the basis for

> these molecular cysteine switches, drawing on the NMDA receptor as an

> exemplary protein, and proposes a molecular model for the action of

> S-nitrosylation based on recently derived crystal structures.

>

> Publication Types:

>

> * Review

> * Review, Tutorial

>

>

> PMID: 12183209 [PubMed - indexed for MEDLINE]

>

> Biophys J. 2001 May;80(5):2152-66. Related Articles, Links

> Click here to read

> Desensitization of NMDA receptor channels is modulated by glutamate

> agonists.

>

> Nahum-Levy R, Lipinski D, Shavit S, Benveniste M.

>

> Department of Physiology and Pharmacology, Sackler School of

> Medicine, Tel Aviv University, Ramat Aviv, 69978 Israel.

>

> Two distinct forms of desensitization have been characterized for

> N-methyl-D-aspartate (NMDA) receptors. One form results from a weakening

> of agonist affinity when channels are activated whereas the other form of

> desensitization results when channels enter a long-lived nonconducting

> state. A weakening of glycine affinity upon NMDA receptor activation has

> been reported. Cyclic reaction schemes for NMDA receptor activation

> require that a concomitant affinity shift should be observed for

> glutamate agonists. In this study, measurements of peak and steady-state

> NMDA receptor currents yielded EC50 values for glutamate that differed by

> 1.9-fold, but no differences were found for another agonist,

> L-cysteine-S-sulfate (LCSS). Simulations show that shifts in EC50 values

> may be masked by significant degrees of desensitization resulting from

> channels entering a long-lived nonconducting state. Simulations also show

> that a decrease in the degree of desensitization with increasing agonist

> concentration is a good indicator for the existence of desensitization

> resulting from a weakening of agonist affinity. Both glutamate and LCSS

> exhibited this trend. An affinity difference of three- to eightfold

> between high-and low-affinity agonist-binding states was estimated from

> fitting of dose-response data with models containing both types of

> desensitization. This indicates that activation of NMDA receptors causes

> a reduction in both glutamate and glycine affinities.

>

> PMID: 11325718 [PubMed - indexed for MEDLINE]

>

>Neurotoxicology. 2002 Dec;23(6):755-9. Related Articles, Links

>

> The consequences of methylmercury exposure on interactive functions

> between astrocytes and neurons.

>

> JW, Shanker G, Tan KH, Aschner M.

>

> Interdisciplinary Program in Neuroscience, Department of Physiology

> and Pharmacology, Wake Forest University School of Medicine,

> Winston-Salem, NC 27157-1083, USA.

>

> Methylmercury (MeHg) is a highly neurotoxic, environmentally

> ubiquitous chemical that exerts its toxic effects by largely unknown

> mechanisms. Maintenance of optimal intracellular concentrations of

> glutathione (GSH) is vital for cellular defenses against damage from free

> radicals. Since astrocytes play an essential role in providing GSH

> precursors to neurons, studies were directed at the effect of MeHg on

> cystine transport in both cell types. Astrocytes accumulated cystine via

> three independent transporters, referred to as system XAG-, system XC-,

> and gamma-glutamyltranspeptidase (GGT). In contrast, neurons accumulated

> cystine exclusively via system XC- and GGT. MeHg potently inhibited

> cystine uptake in astrocytes (but not in neurons), and this effect could

> be fully accounted for by inhibition of the system XAG- transporter. The

> transport of glutamate in astrocytes is also inhibited by reactive oxygen

> species (ROS). Accordingly, additional studies examined the ability of

> thiol reducing or oxidizing agents to inhibit the astrocytic transport of

> 3H-D-aspartate, a glutamate analog. The antioxidant catalase

> significantly attenuated MeHg-induced inhibition of astrocytic

> 3H-aspartate uptake. Combinedly, these studies suggest that inhibition of

> cystine uptake and decreased astrocytic GSH levels and efflux reduce the

> availability of precursors for GSH synthesis in neurons. In addition,

> MeHg-induced generation of H2O2 plays a role in the inhibition of

> astrocytic glutamate transport. These effects likely increase neuronal

> vulnerability to MeHg-induced oxidative stress, and excess N-methyl

> D-aspartate (NMDA) receptor activation leading to neuronal demise.

>

> Publication Types:

>

> * Review

> * Review, Tutorial

>

>

> PMID: 12520765 [PubMed - indexed for MEDLINE]

>

>Biochem Biophys Res Commun. 2004 Nov 5;324(1):133-9. Related Articles,

>Links

> Click here to read

> Rodent lymphocytes express functionally active glutamate receptors.

>

> Boldyrev AA, Kazey VI, Leinsoo TA, Mashkina AP, Tyulina OV,

> P, Tuneva JO, Chittur S, Carpenter DO.

>

> Department of Biochemistry, Center for Molecular Medicine and

> International Biotechnological Center, M.V. Lomonosov Moscow State

> University, 119992 Moscow, Russia.

>

> RT-PCR demonstrated that ionotropic (iGluR NR1) and metabotropic

> (mGluR Group III) glutamate receptors are expressed in rodent

> lymphocytes. Flow cytometry showed that activation of iGluR NR1 by

> N-methyl-D-aspartate (NMDA) increased intracellular free calcium and

> reactive oxygen species (ROS) levels and activated caspase-3. The latter

> effect was attenuated by the NMDA antagonist,

> 5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801), by

> the antioxidant N-acetylcysteine and by cyclosporin A. Treatment with

> L-2-amino-4-phosphonobutyric acid (L-AP4), an mGluR Group III agonist,

> increased lymphocyte ROS levels but to a lower extent than did NMDA.

> Activation of lymphocytes with both NMDA and L-AP4 caused a synergistic

> increase in ROS levels and induced necrotic cellular death without

> elevating the caspase-3 activation observed in the presence of NMDA

> alone. These results show that lymphocyte iGluR NR1 and mGluR Group III

> receptors may be involved in controlling rodent lymphocyte functions and

> longevity as they regulate events in cell proliferation, maturation, and

death.

>

> PMID: 15464993 [PubMed - indexed for MEDLINE]

>

>J Cell Biochem. 2003 Oct 1;90(2):424-36. Related Articles, Links

> Click here to read

> NMDA glutamate receptors are expressed by osteoclast precursors and

> involved in the regulation of osteoclastogenesis.

>

> Merle B, Itzstein C, Delmas PD, Chenu C.

>

> INSERM Unit 403, Hopital E. Herriot, Pavillon F, 69437 LYON Cedex 03,

> France. merle@...

>

> We previously identified functional N-methyl-D-aspartate (NMDA)

> glutamate receptors in mature osteoclasts and demonstrated that they are

> involved in bone resorption in vitro. In the present work, we studied the

> expression of NMDA receptors (NMDAR) by osteoclast precursors and their

> role in osteoclastogenesis using two in vitro models, the murine

> myelomonocytic RAW 264.7 cell line and mouse bone marrow cells, both of

> which differentiate into osteoclasts in the presence of macrophage

> colony-stimulating factor (M-CSF) and Rank ligand (RankL). Using RT-PCR

> analysis with specific probes, we showed that RAW 264.7 cells and mouse

> bone marrow cells express mRNA of NMDAR subunits NMDA receptor 1 (NR1)

> and NMDA receptor 2 (NR2) A, B, and D. These subunits are expressed all

> along the differentiation sequence from undifferentiated precursors to

> mature resorbing osteoclasts. Semi-quantitative PCR analysis showed no

> regulation of the expression of these subunits during the differentiation

> process. Two specific non competitive antagonists of NMDAR, MK801 and

> DEP, dose-dependently inhibited osteoclast formation in both models,

> indicating that osteoclastogenesis requires the activation of NMDAR

> expressed by osteoclast precursors. MK801 had no effect when added only

> during the first 2 days of culture, suggesting that NMDAR are rather

> involved in the late stages of osteoclast formation. Finally, we

> demonstrated using Western-blotting and immunofluorescence that

> activation of NMDAR in RAW 264.7 cells by specific agonists induces

> nuclear translocation of NF-kappa B, a factor required for osteoclast

> formation. Altogether, our results indicate that osteoclast precursors

> express NMDAR that are involved in the osteoclast differentiation process

> through activation of the NF-kappa B pathway. Copyright 2003 Wiley-Liss, Inc.

>

> PMID: 14505357 [PubMed - indexed for MEDLINE]

>

>

> J Neurosci Res. 2005 Feb 1;79(3):375-82. Related Articles, Links

> Click here to read

> Dual effect of DL-homocysteine and S-adenosylhomocysteine on brain

> synthesis of the glutamate receptor antagonist, kynurenic acid.

>

> Luchowska E, Luchowski P, Paczek R, Ziembowicz A, Kocki T, Turski WA,

> Wielosz M, Lazarewicz J, Urbanska EM.

>

> Department of Pharmacology and Toxicology, Skubiszewski Medical

> University of Lublin, Lublin, Poland.

>

> Increased serum level of homocysteine, a sulfur-containing amino

> acid, is considered a risk factor in vascular disorders and in dementias.

> The effect of homocysteine and metabolically related compounds on brain

> production of kynurenic acid (KYNA), an endogenous antagonist of

> glutamate ionotropic receptors, was studied. In rat cortical slices,

> DL-homocysteine enhanced (0.1-0.5 mM) or inhibited (concentration

> inducing 50% inhibition [iC50]=6.4 [5.5-7.5] mM) KYNA production. In vivo

> peripheral application of DL-homocysteine (1.3 mmol/kg intraperitoneally)

> increased KYNA content (pmol/g tissue) from 8.47 +/- 1.57 to 13.04 +/-

> 2.86 (P <0.01; 15 min) and 11.4 +/- 1.72 (P <0.01; 60 min) in cortex, and

> from 4.11 +/- 1.54 to 10.02 +/- 3.08 (P <0.01; 15 min) in rat

> hippocampus. High concentrations of DL-homocysteine (20 mM) applied via

> microdialysis probe decreased KYNA levels in rabbit hippocampus; this

> effect was antagonized partially by an antagonist of group I metabotropic

> glutamate receptors, LY367385. In vitro, S-adenosylhomocysteine acted

> similar to but more potently than DL-homocysteine, augmenting KYNA

> production at 0.03-0.08 mM and reducing it at > or =0.5 mM. The

> stimulatory effect of S-adenosylhomocysteine was abolished in the

> presence of the L-kynurenine uptake inhibitors L-leucine and

> L-phenyloalanine. Neither the N-methyl-D-aspartate (NMDA) antagonist CGS

> 19755 nor L-glycine influenced DL-homocysteine- and

> S-adenosylhomocysteine-induced changes of KYNA synthesis in vitro.

> DL-Homocysteine inhibited the activity of both KYNA biosynthetic enzymes,

> kynurenine aminotransferases (KATs) I and II, whereas

> S-adenosylhomocysteine reduced only the activity of KAT II. L-Methionine

> and L-cysteine, thiol-containing compounds metabolically related to

> homocysteine, acted only as weak inhibitors, reducing KYNA production in

> vitro and inhibiting the activity of KAT II (L-cysteine) or KAT I

> (L-methionine). The present data suggest that DL-homocysteine

> biphasically modulates KYNA synthesis. This seems to result from

> conversion of compound to S-adenosylhomocysteine, also acting dually on

> KYNA formation, and in part from the direct interaction of homocysteine

> with metabotropic glutamate receptors and KYNA biosynthetic enzymes. It

> seems probable that hyperhomocystemia-associated brain dysfunction is

> mediated partially by changes in brain KYNA level.

>

> PMID: 15605380 [PubMed - in process]

>

>Curr Opin Pharmacol. 2004 Feb;4(1):12-7. Related Articles, Links

> Click here to read

> The kynurenine pathway of tryptophan degradation as a drug target.

>

> Schwarcz R.

>

> land Psychiatric Research Center, University of land School

> of Medicine, Baltimore, land 21228, USA. rschwarc@...

>

> In mammalian cells, the essential amino acid tryptophan is degraded

> primarily by the kynurenine pathway, a cascade of enzymatic steps

> containing several biologically active compounds. Metabolites of this

> pathway, collectively termed 'kynurenines', have been shown to be

> involved in many diverse physiological and pathological processes. In

> particular, fluctuations in the levels of kynurenines have discrete

> effects on the nervous and immune systems. A considerable number of

> pharmacological tools have recently become available to probe the

> kynurenine pathway experimentally. Some of these 'kynurenergic' agents

> can be envisioned to be of therapeutic value, especially in the treatment

> of diseases that are associated with impaired kynurenine pathway metabolism.

>

> Publication Types:

>

> * Review

> * Review, Tutorial

>

>

> PMID: 15018833 [PubMed - indexed for MEDLINE]

> Biosci Biotechnol Biochem. 1995 Nov;59(11):2060-3. Related Articles,

> Links

>

> Effects of vitamin B6 deficiency on the conversion ratio of

> tryptophan to niacin.

>

> Shibata K, Mushiage M, Kondo T, Hayakawa T, Tsuge H.

>

> Department of Human Health Science, Faculty of Human Sciences, Osaka

> International University for Women, Japan.

>

> To investigate how vitamin B6 (B6) deficiency affects the whole

> metabolism of tryptophan-niacin, rats were fed for 19 days with each of

> the following four kinds of diets; a complete 20% casein diet (control

> diet), the control diet without B6, the control diet without nicotinic

> acid, and the control diet without nicotinic acid and B6, and the urinary

> excretion of such tryptophan metabolites as kynurenic acid, xanthurenic

> acid, nicotinamide, N1-methylnicotinamide,

> N1-methyl-2-pyridone-5-carboxamide, and

> N1-methyl-4-pyridone-3-carboxamide each and the enzyme activities

> involved in tryptophan-niacin pathway were measured. The urinary

> excretion of kynurenic acid decreased while that of xanthurenic acid

> increased drastically in the two B6-deficient groups, when compared with

> the B6-containing groups. These results indicate that the rats fed with

> the B6-free diets were in the vitamin-deficient state. The conversion

> ratio was calculated from the ratio of the urinary excretion of sum of

> nicotinamide, N1-methylnicotinamide, N1-methyl-2-pyridone-5-carboxamide,

> and N1-methyl-4-pyridone-3-carboxamide, to the Trp intake. The ratio was

> statistically lower in the B6-free diet than in the B6-containing diet

> under the niacin-free conditions.

>

> PMID: 8541642 [PubMed - indexed for MEDLINE]

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[Guest guest]

>

> ,

>

> This article below is suggesting some sulfurish issues that may

account for

> alternative reactions at glutamate receptors. I don't know if this

has to

> do with the sort of reactions you have heard described with MSG and

maybe

> some related compounds.

>

We are sulfur intolerant as well. We see an increase in problems when

we consume any sulfur foods.