Tetrameric (G<sub>4</sub>) Acetylcholinesterase: Structure, Localization, and Physiological Regulation

Fernández, Hugo L.; Moreno, Ricardo D.; Inestrosa, Nibaldo C.

doi:10.1046/j.1471-4159.1996.66041335.x

Cited by 65 publications

(29 citation statements)

References 55 publications

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“…The amphiphiphilic cholinesterase contains G4 catalytic tetramer and one non-catalytic subunit P (ref. 54 ). The P subunit has a molecular weight 20 kDa and it is asymmetrically bound to two G subunits.…”

Section: Acetylcholinesterasementioning

confidence: 99%

Cholinesterases, a Target of Pharmacology and Toxicology

Pohanka¹

2011

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

321

219

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Background. Cholinesterases are a group of serine hydrolases that split the neurotransmitter acetylcholine (ACh) and terminate its action. Of the two types, butyrylcholinesterase and acetylcholinesterase (AChE), AChE plays the key role in ending cholinergic neurotransmission. Cholinesterase inhibitors are substances, either natural or man-made that interfere with the break-down of ACh and prolong its action. Hence their relevance to toxicology and pharmacology.Methods and Results. The present review summarizes current knowledge of the cholinesterases and their inhibition. Particular attention is paid to the toxicology and pharmacology of cholinesterase-related inhibitors such as nerve agents (e.g. sarin, soman, tabun, VX), pesticides (e.g. paraoxon, parathion, malathion, malaoxon, carbofuran), selected plants and fungal secondary metabolites (e.g. aflatoxins), drugs for Alzheimer's disease (e.g. huperzine, metrifonate, tacrine, donepezil) and Myasthenia gravis (e.g. pyridostigmine) treatment and other compounds (propidium, ethidium, decamethonium).Conclusions. The crucial role of the cholinesterases in neural transmission makes them a primary target of a large number of cholinesterase-inhibiting drugs and toxins. In pharmacology, this has relevance to the treatment of neurodegenerative disorders.

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Section: Acetylcholinesterasementioning

confidence: 99%

Cholinesterases, a Target of Pharmacology and Toxicology

Pohanka¹

2011

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

321

219

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“…The proportion of membrane-bound tetramers increases steadily during development and becomes predominant in the adult (5). These amphiphilic tetramers (G 4 a ) form clusters on the surface of cultured neurons (6) and represent the physiologically active AChE species (7)(8)(9).…”

mentioning

confidence: 99%

Two Distinct Proteins Are Associated with Tetrameric Acetylcholinesterase on the Cell Surface

Perrier¹,

Cousin²,

Boschetti³

et al. 2000

Journal of Biological Chemistry

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In mammalian brain, acetylcholinesterase (AChE) exists mostly as a tetramer of 70-kDa catalytic subunits that are linked through disulfide bonds to a hydrophobic subunit P of approximately 20 kDa. To characterize P, we reduced the disulfide bonds in purified bovine brain AChE and sequenced tryptic fragments from bands in the 20-kDa region. We obtained sequences belonging to at least two distinct proteins: the P protein and another protein that was not disulfide-linked to catalytic subunits. Both proteins were recognized in Western blots by antisera raised against specific peptides. We cloned cDNA encoding the second protein in a cDNA library from bovine substantia nigra and obtained rat and human homologs. We call this protein mCutA because of its homology to a bacterial protein (CutA). We could not demonstrate a direct interaction between mCutA and AChE in vitro in transfected cells. However, in a mouse neuroblastoma cell line that produced membrane-bound AChE as an amphiphilic tetramer, the expression of mCutA antisense mRNA eliminated cell surface AChE and decreased the level of amphiphilic tetramer in cell extracts. mCutA therefore appears necessary for the localization of AChE at the cell surface; it may be part of a multicomponent complex that anchors AChE in membranes, together with the hydrophobic P protein.

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“…The enzymatic activity of Ache is increased in tumors such as breast, ovarian and bladder cancers, leukemias, glioblastomas, meningiomas, and brain neoplasmas. During tumor growth and progression, Ache genes are amplified and the protein products are abnormally expressed, displaying altered isoforms (variants) and glycosylation patterns [70][71][72]. Breast cancer epithelia synthesize Ache in the cytoplasmic compartment; Ache is then transported and inserted into the plasma membrane anchored to the glycolipid glycophosphidylinositol [73].…”

Section: Tumor Acetylcholinesterases and Gipmentioning

confidence: 99%

Review of Growth Inhibitory Peptide as a Biotherapeutic agent for tumor growth, adhesion, and metastasis

Muehlemann

Miller

Dauphinée

et al. 2005

Cancer Metastasis Rev

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This review surveys the biological activities of an alpha-fetoprotein (AFP) derived peptide termed the Growth Inhibitory Peptide (GIP), which is a synthetic 34 amino acid segment produced from the full length 590 amino acid AFP molecule. The GIP has been shown to be growth-suppressive in both fetal and tumor cells but not in adult terminally-differentiated cells. The mechanism of action of this peptide has not been fully elucidated; however, GIP is highly interactive at the plasma membrane surface in cellular events such as endocytosis, cell contact inhibition and cytoskeleton-induced cell shape changes. The GIP was shown to be growth-suppressive in nine human tumor types and to suppress the spread of tumor infiltrates and metastases in human and mouse mammary cancers. The AFP-derived peptide and its subfragments were also shown to inhibit tumor cell adhesion to extracellular matrix (ECM) proteins and to block platelet aggregation; thus it was expected that the GIP would inhibit cell spreading/migration and metastatic infiltration into host tissues such as lung and pancreas. It was further found that the cyclic versus linear configuration of GIP determined its biological and anti-cancer efficacy. Genbank amino acid sequence identities with a variety of integrin alpha/beta chain proteins supported the GIP's linkage to inhibition of tumor cell adhesion and platelet aggregation. The combined properties of tumor growth suppression, prevention of tumor cell-to-ECM adhesion, and inhibition of platelet aggregation indicate that tumor-to-platelet interactions present promising targets for GIP as an anti-metastatic agent. Finally, based on cholinergic studies, it was proposed that GIP could influence the enzymatic activity of membrane acetylcholinesterases during tumor growth and metastasis. It was concluded that the GIP derived from full-length AFP represents a growth inhibitory motif possessing instrinsic properties that allow it to interfere in cell surface events such as adhesion, migration, metastasis, and aggregation of tumor cells.

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Tetrameric (G₄) Acetylcholinesterase: Structure, Localization, and Physiological Regulation

Cited by 65 publications

References 55 publications

Cholinesterases, a Target of Pharmacology and Toxicology

Cholinesterases, a Target of Pharmacology and Toxicology

Two Distinct Proteins Are Associated with Tetrameric Acetylcholinesterase on the Cell Surface

Review of Growth Inhibitory Peptide as a Biotherapeutic agent for tumor growth, adhesion, and metastasis

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Tetrameric (G4) Acetylcholinesterase: Structure, Localization, and Physiological Regulation

Cited by 65 publications

References 55 publications

Cholinesterases, a Target of Pharmacology and Toxicology

Cholinesterases, a Target of Pharmacology and Toxicology

Two Distinct Proteins Are Associated with Tetrameric Acetylcholinesterase on the Cell Surface

Review of Growth Inhibitory Peptide as a Biotherapeutic agent for tumor growth, adhesion, and metastasis

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Tetrameric (G₄) Acetylcholinesterase: Structure, Localization, and Physiological Regulation