Interactions of Acetylcholine Receptors with Organic Mercury Compounds

Eldefrawi, Mohyee E.; Mansour, Nabil; Eldefrawi, Amira T.

doi:10.1007/978-1-4684-3279-4_20

Cited by 36 publications

(17 citation statements)

References 35 publications

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“…Thus, the present observation of a decrease in carbachol-stimulated PI hydrolysis at PND 1 is consistent with a decrease in muscarinic receptors in MeHg-exposed rats. Both inorganic mercury and MeHg have been reported to directly inhibit muscarinic receptor binding, and it was suggested that the molecular mechanism of this effect might involve the interaction of mercurials with essential sulfhydryl groups located at the binding site of the muscarinic receptor (Abd-Elfattah and Shamoo, 1981;Eldefrawi et al, 1977). The high affinity of mercury and MeHg for sulfhydryl groups on cysteine residues (Hughes, 1957;Mullaney et al, 1994) and the numerous cysteine residues which are required for biological activity of Trk receptors (Bothwell, 1995;McDonald and Chao, 1995) suggests a common mechanism for the inhibition of muscarinic and Trk receptors, which could lead to a corresponding decrease in receptor signaling.…”

Section: Discussionmentioning

confidence: 99%

Gestational exposure to methylmercury alters neurotrophin- and carbachol-stimulated phosphatidylinositide hydrolysis in cerebral cortex of neonatal rats

1999

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Neurotrophin-stimulated signal transduction through the Trk receptors has been implicated in the development and survival of the nervous system. Phospholipase Cy (PLCy) is an early downstream effector for the Trk receptors, and catalyzes the hydrolysis of phosphatidylinositides (PIs) to inositol phosphates (1Ps) and diacylglycerol. The current study demonstrated that PI hydrolysis can be used as a measure of Trk stimulation in slices from neonatal rat brain, and examined changes in the ontogeny of neurotrophin-stimulated PI hydrolysis in animals exposed to MeHg during gestation. Neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF) stimulated PI hydrolysis in neocortical and cerebellar slices from neonatal rats in a concentration-dependent manner (30-1000ng/ml). The neurotrophinstimulated PI hydrolysis was completely blocked by K-252a, a compound known to inhibit Trk autophosphorylation. To examine the effects of MeHg on PI hydrolysis, Long-Evans dams were dosed p.o. on gestational days 6-15 with 0 or 2 mg/kg/day MeHg dissolved in saline. Pups were sacrificed on postnatal days (PND) 1, 4, 10, 14, and 21 and brain slices prepared from the neocortex and cerebellum. Neurotrophin-stimulated PI hydrolysis was highest on PND 1-4 and decreased with age in slices from both regions. Prior exposure to MeHg had no effect on NT-3 or BDNF-stimulated PI hydrolysis in the cerebellum; however, in the neocortex carbacholstimulated PI hydrolysis and NT-3-stimulated PI hydrolysis were decreased on PND 1. In addition, NT-3-stimulated PI hydrolysis was increased on PND 14 compared to controls. Nerve growth factor (NGF), which had no effect in controls, increased PI hydrolysis in MeHg exposed animals. Acute exposure to 10 ~tM MeHg increased basal PI hydrolysis in cortical slices and increased NT-3-and BDNF-stimulated PI hydrolysis in slices from the cerebellum. These data indicate that gestational exposure to MeHg can alter neurotrophin signaling in the neocortex at early postnatal times.

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Section: Discussionmentioning

confidence: 99%

Gestational exposure to methylmercury alters neurotrophin- and carbachol-stimulated phosphatidylinositide hydrolysis in cerebral cortex of neonatal rats

1999

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“…Eldefrawi et al (1977) reported that 10 M methylmercury inhibited binding of [ 3 H]nicotine to rat brain membranes by 60%. Methylmercury (10 M) was also shown to suppress depolarizing responses to nicotine in N1E-115 neuroblastoma cells (Quandt et al, 1982).…”

Section: Discussionmentioning

confidence: 99%

“…Several types of receptors and ion channels have been reported to be directly affected by mercury compounds. Methylmercury blocks the binding of ACh to the Torpedo californica electric organ nAChRs and the binding of nicotine to nAChRs expressed in rat brain (Eldefrawi et al, 1977). Methylmercury also suppresses nicotinic responses in neuroblastoma cells (Quandt et al, 1982).…”

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confidence: 99%

Modulation of Neuronal Nicotinic Acetylcholine Receptors by Mercury

Mirzoian

Luetje

2002

J Pharmacol Exp Ther

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Mercuric chloride exerted a biphasic modulatory effect on rat neuronal nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus laevis oocytes as heteromers of the ␣3 or ␣4 and ␤2 or ␤4 subunits. The degree of modulation was subunit-dependent, with ␤4-containing receptors displaying greater potentiation and ␣4-containing receptors displaying greater inhibition. Thus, ␣4␤4 receptors displayed both robust potentiation and robust inhibition. During prolonged coapplication of HgCl 2 , first potentiation then inhibition of the acetylcholine (ACh) response was observed. Upon coapplication of 1 M HgCl 2 , a 2-fold increase in ACh-induced current was achieved in 55 Ϯ 1 s. With continued HgCl 2 application, the ACh response was slowly inhibited until, after 5 min, less than 10% of the initial response remained. By measuring potentiation at its peak and inhibition 5 min after the start of HgCl 2 coapplication, we obtained EC 50 and IC 50 values of 262 Ϯ 75 and 430 Ϯ 72 nM, respectively. HgCl 2 potentiation was voltage-dependent, increasing at more positive holding potentials. Upon washout of mercury chloride, potentiation reversed with a t 1/2 of 4.6 min. Inhibition reversed more slowly, with less than half the initial response recovered after 15 min of wash. Although free cysteine residues are common targets for mercury, elimination of all free cysteines located in the extracellular domains of the ␣4 and ␤4 subunits did not alter the effects of mercuric chloride. Potentiation and inhibition of neuronal nAChRs may occur through action at a transmembrane or cytoplasmic location after passive diffusion of mercuric chloride across the plasma membrane.

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“…Recently, the neuronal cholinergic system was postulated to be an important target for MeHg toxicity (Atchison, 2005). Substantial evidences indicate that the neuronal cholinergic muscarinic system is altered by exposure to low concentrations of MeHg (Basu et al, 2006;Castoldi et al, 1996;Coccini et al, 2000;Eldefrawi et al, 1977;Von Burg et al, 1980). Currently, developmental neurotoxicity is considered to be the most sensitive adverse health effect of MeHg (Risher et al, 2002).…”

Section: Methylmercury (Mehg) Is An Environmental Toxicant That Is Knmentioning

confidence: 95%

Involvement of the Lymphocytic Muscarinic Acetylcholine Receptor in Methylmercury-Induced c-Fos Expression and Apoptosis in Human Leukemic T Cells

Suriyo

Thiantanawat

Chaiyaroj

et al. 2008

Journal of Toxicology and Environmental Health, Part A

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Methylmercury (MeHg) is an environmental toxicant that is known to induce lymphocyte apoptosis; however, little is known about the molecular mechanism involved. Data showed that MOLT-3 cells were more sensitive to MeHg-induced cytotoxic effects than Jurkat clone E6-1 cells, suggesting that the lymphocytic muscarinic cholinergic system may be involved since the expressions of five subtypes (M1-M5) of muscarinic acetylcholine receptor (mAChR) in MOLT-3 cells are higher than in Jurkat cells. The role of mAChR-linked pathways in MeHg-induced apoptosis in human leukemic T cells was examined in this study. Treatment of the MOLT-3 cells with 1 microM MeHg produced induction of c-Fos expression, apoptotic cell death, and downregulation of mAChR. MeHg-induced c-Fos expression was significantly reduced by pretreatment with atropine (a nonselective mAChR antagonist), or 4-DAMP (a selective M1/M3 mAChR antagonist), whereas pirenzipine (a selective M1 mAChR antagonist) or himbazine (a selective M2/M4 mAChR antagonist) did not reduce this induction, suggesting that MeHg-induced c-Fos expression through the activation of the mAChR, at least M3 subtype, is involved. Pretreatment with 4-DAMP or SB 203580 (a specific p38 inhibitor) resulted in decreases in the level of phosphorylated p38, c-Fos expression, and apoptotic cell death induced by MeHg. Taken together, these data suggest that the mAChR-p38-dependent pathway participates in the increase of c-Fos expression, which is involved in MeHg-induced lymphocyte apoptosis. In addition, a noncytotoxic concentration of MeHg (0.1 microM) inhibited PHA/PMA-stimulated interleukin (IL)-2 production, and this inhibition was reversed by pretreatment with atropine or 4-DAMP. Overall, this study provides initial evidence that MeHg may alter the immune system by targeting the lymphocytic mAChR.

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Interactions of Acetylcholine Receptors with Organic Mercury Compounds

Cited by 36 publications

References 35 publications

Gestational exposure to methylmercury alters neurotrophin- and carbachol-stimulated phosphatidylinositide hydrolysis in cerebral cortex of neonatal rats

Gestational exposure to methylmercury alters neurotrophin- and carbachol-stimulated phosphatidylinositide hydrolysis in cerebral cortex of neonatal rats

Modulation of Neuronal Nicotinic Acetylcholine Receptors by Mercury

Involvement of the Lymphocytic Muscarinic Acetylcholine Receptor in Methylmercury-Induced c-Fos Expression and Apoptosis in Human Leukemic T Cells

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