Muscarinic acetylcholine receptor and membrane dynamics: A possible factor in age-related memory dysfunction.
Item
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Title
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Muscarinic acetylcholine receptor and membrane dynamics: A possible factor in age-related memory dysfunction.
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Identifier
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AAI8914788
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identifier
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8914788
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Creator
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Schoenheimer, Joyce Anne.
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Contributor
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Adviser: Arnold S. Lippa
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Date
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1988
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Language
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English
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Publisher
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City University of New York.
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Subject
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Psychology, Psychobiology
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Abstract
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The muscarinic acetylcholine receptor (mAChR) has been characterised as a protein containing seven membrane spanning alpha-helical segments with binding sites deep within segments two and three. This model suggests a dynamic relationship between membrane microviscosity and receptor conformation. Hippocampal mAChR antagonist and agonist binding was therefore characterized and the affect of manipulating membrane viscosity alone or in combination with membrane composition was determined.;Decreasing membrane fluidity by decreasing incubation temperatures did not affect the ability of ligands to induce a conformational change in the receptor. However, increases in the affinity of the receptor for the mAChR antagonist atropine and the agonists carbachol and oxotremorine were observed. The K{dollar}\sb{lcub}\rm D{rcub}{dollar} for {dollar}\sp3{dollar}H-QNB was unaltered, a small significant increase in the B{dollar}\sb{lcub}\rm max{rcub}{dollar} was observed at 15{dollar}\sp\circ{dollar}C. Contrarily, AL721 treatment (a membrane fluidizer that extracts cholesterol) appeared to affect the ability of oxotremorine to induce a conformational change in the receptor. Oxotremorine bound to a single state of the mAChR in the control condition, indicating an inability to induce a conformational change, and to more than one state of the mAChR following AL721 treatment, suggesting a conformational change. Carbachol and {dollar}\sp3{dollar}H-QNB binding were unaltered.;The interrelationship between membrane fluidity and receptor conformation may have clinical applications; increased membrane rigidity, and decreased responsiveness to fluidizing agents occurs with age. AL721 effects on {dollar}\sp3{dollar}H-QNB binding and oxotremorine binding in aged membranes were determined. No significant changes in binding were observed. A decreased sensitivity of aged membranes to AL721 in combination with a decreased effect of fluidizing on oxotremorine binding suggests that these two events were related in the young animals. The difference apparently lies in the flexibility of the aged system, since the control values for {dollar}\sp3{dollar}H-QNB and oxotremorine binding in young and old systems were equal.;In summary, manipulation of membrane microviscosity with temperature caused a change in receptor affinity, while fluidization with AL721 caused a change in the receptor conformation. Finally data from aged tissue suggests the possibility that aged membranes are less responsive to their environment and less affected by changes in membrane composition.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
