Alcohol action on a neuronal membrane receptor: evidence for a direct interaction with the receptor protein.

Li, Chaoying; Peoples, Robert W.; Weight, Forrest F.

doi:10.1073/pnas.91.17.8200

Cited by 110 publications

(75 citation statements)

References 22 publications

(34 reference statements)

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“…-amino butyric acid A (GABA A ), glycine, glutamate, norepinephrine, DA, serotonin, acetylcholine and opiate receptors), as well as transporters (adenosine, norepinephrine, DA, serotonin transporters). Particularly, ion channels including the L-type voltage-gated Ca 2+ channels (VGCC) [127] and the ligandgated channels of the main amino acid neurotransmitter systems of the brain -the inhibitory GABA and the excitatory glutamate -seem to be highly sensitive to the acute effect of ethanol at relevant (5 -100 mM) concentrations [26,63,70,118,123].…”

Section: Ethanol and Nmda Receptorsmentioning

confidence: 99%

Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

Nagy

Kolok²,

Boros³

et al. 2005

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Long-term alcohol exposure gives rise to development of physical dependence on alcohol in consequence of changes in certain neurotransmitter functions. Accumulating evidence suggests that the glutamatergic neurotransmitter system, especially the N-methyl-D-aspartate (NMDA) type of glutamate receptors is a particularly important site of ethanol's action, since ethanol is a potent inhibitor of the NMDA receptors (NMDARs) and prolonged ethanol exposition leads to a compensatory "upregulation" of NMDAR mediated functions supposedly contributing to the occurrence of ethanol tolerance, dependence as well as the acute and delayed signs of ethanol withdrawal.Recently, expression of different types of NMDAR subunits was found altered after long-term ethanol exposure. Especially, the expression of the NR2B and certain splice variant forms of the NR1 subunits were increased in primary neuronal cultures treated intermittently with ethanol. Since NMDA ion channels with such an altered subunit composition have increased permeability for calcium ions, increased agonist sensitivity, and relatively slow closing kinetics, the abovementioned alterations may underlie the enhanced NMDAR activation observed after long-term ethanol exposure. In accordance with these changes, the inhibitory potential of NR2B subunit-selective NMDAR antagonists is also increased, demonstrating excellent potency against alcohol withdrawal-induced in vitro cytotoxicity. Although in vivo data are few with these compounds, according to the effectiveness of the classic NMDAR antagonists in attenuation, not only the physical symptoms,but also some affective and motivational components of alcohol withdrawal, novel NR2B subunit selective NMDAR antagonists may offer a preferable alternative in the pharmacotherapy of alcohol dependence.

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Section: Ethanol and Nmda Receptorsmentioning

confidence: 99%

Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

Nagy

Kolok²,

Boros³

et al. 2005

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“…If ethanol inhibits Ll-mediated cellcell adhesion by disordering membrane lipids, then the potency of higher alcohols should increase as a linear function of chain length and lipid solubility. In contrast, if ethanol interacts with specific protein binding sites within L1, then a cutoff should be demonstrable above which higher chain-length alcohols no longer interact with L1, despite increasing membrane disorder (19,37,55). To explore these two possibilities, we performed aggregation assays of clone 6g3f-L1 in the absence or presence of n-alcohols of one to eight carbon atoms.…”

Section: Cut-off Effect For N-alcohol Inhibition Of Ll-mediated Cell-mentioning

confidence: 99%

Alcohol inhibits cell-cell adhesion mediated by human L1 [published erratum appears in J Cell Biol 1996 Jun;133(5):1139-40]

Ramanathan

Wilkemeyer

Mittal

et al. 1996

The Journal of Cell Biology

167

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Abstract. Mental retardation, hydrocephalus, and agenesis of the corpus callosum are observed both in fetal alcohol syndrome (FAS) and in children with mutations in the gene for the cell adhesion molecule L1. We studied the effects of ethanol on cell-cell adhesion in mouse fibroblasts transfected with human L1. Ll-transfected fibroblasts exhibited increased cell-cell adhesion compared with wild-type or vector-transfected controls. Ethanol potently and completely inhibited Ll-mediated adhesion both in transfected L cells and NIH/3T3 cells. Half-maximal inhibition was observed at 7 mM ethanol, a concentration achieved in blood and brain after ingesting one alcoholic beverage. In contrast, ethanol did not inhibit the adhesion of fibroblasts transfected with vector alone or with N-CAM-140. Ll-mediated cell-cell adhesion was inhibited with increasing potency by n-propanol and n-butanol, but was not inhibited at all by n-alcohols of 5 to 8 carbons, acetaldehyde, or acetate, suggesting that ethanol interacts directly with a small hydrophobic pocket within L1. Phenylalanine, teratogenic anticonvulsants, and high concentrations of glucose did not inhibit Ll-mediated cell-cell adhesion. Ethanol also inhibited potently the heterotypic adhesion of rat cerebellar granule cells to a monolayer of Ll-transfected NIH/3T3 cells, but had no effect on their adhesion to N-CAM-140 or vector-transfected NIH/3T3 cells. Because L1 plays a role in both neural development and learning, ethanol inhibition of Ll-mediated cell-cell interactions could contribute to FAS and ethanol-associated memory disorders. FETAL alcohol syndrome (FAS) 1 is one of the most common recognizable syndromes associated with mental retardation in the Western world (1). The full syndrome, characterized by growth retardation, neurological abnormalities, and facial malformations, occurs in N5% of the offspring of alcoholic women (1, 72). Neuropathological examination and neuroimaging of children with FAS have disclosed a spectrum of neurodevelopmental abnormalities, including hydrocephalus, agenesis of the corpus callosum, neuronal-glial heterotopias, cerebellar dysplasia, and microcephaly (8,27,62). Some of these lesions arise from disordered migration of neural cells, which has also been demonstrated experimentally in animal models of FAS (45,46 X-linked syndrome associated with mutations in the gene encoding L1, an immunoglobulin cell adhesion molecule (IgCAM) (4,20,28,31,66,74,83). Three overlapping syndromes, X-linked hydrocephalus, MASA syndrome (mental retardation, aphasia, shuffling gait, and adducted thumbs), and X-linked complicated spastic paraplegia, were each mapped to the same region (Xq28) of the X chromosome (32,76,82). A large number of different missense mutations, short deletions, and defects of alternative splicing within the L1 gene have been identified in individuals with these X-linked disorders (83); similar mutations have never been encountered in large numbers of control subjects. A single point mutation in L1 can cause either X-linked hydro...

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“…Many of the recent studies aimed at elucidating the mechanism of action of alcohols and general anesthetics have dealt with the effect of these agents on ligand-gated channels, whose ligand binding site is in a portion of the protein external to the bilayer (1,(7)(8)(9)(10). The superfamily of G protein-coupled receptors has received relatively little study.…”

mentioning

confidence: 99%

Primary Alcohols Modulate the Activation of the G Protein-coupled Receptor Rhodopsin by a Lipid-mediated Mechanism

Mitchell

Lawrence

Litman

1996

Journal of Biological Chemistry

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The visual pigment rhodopsin is a prototypical member of the G protein-coupled receptor superfamily. In this study, we have investigated the effect of a series of n-alcohols on the formation of metarhodopsin II (MII), the photoactivated conformation of rhodopsin, which binds and activates transducin. When rhodopsin was photolyzed in the presence of several n-alcohols, increased MII formation was observed in the order ethanol > butanol > hexanol, whereas longer chain n-alcohols inhibited MII formation with decanol > octanol. The magnitude of the stimulatory effects was greater in a more highly unsaturated phospholipid. Alcohols, which enhanced MII formation also increased phospholipid acyl chain packing free volume, while those that decreased this bilayer property inhibited MII formation. An apparent discontinuity in the effect of these alcohols results when their potency is calculated in terms of the total aqueous alcohol concentration. In sharp contrast, a continuous variation in their behavior is observed, when their potency is calculated in terms of the amount of alcohol partitioned in the membrane. Our findings strongly support a lipid-mediated mechanism of action for alcohols on rhodopsin and, by analogy, for other G protein-coupled receptors.The mechanism of action of alcohols and general anesthetics is generally discussed in terms of two opposing mechanisms. The first involves an alteration of phospholipid bilayer properties by these agents, resulting in a modulation of membrane protein function, while the second is based on the direct interaction with membrane proteins (1, 2). The lipid mechanism was based originally on the observation (3, 4) that anesthetic potency correlated directly with the solubility of an anesthetic in olive oil. Additional support for the lipid mechanism came from the observation that acute exposure of membranes to ethanol resulted in a disordering of the phospholipid acyl chain packing (5). Subsequent experiments demonstrating that the activity of a soluble enzyme, firefly luciferase, could be inhibited by a diverse group of alcohols and general anesthetics (6) have focused attention on the protein binding hypothesis.Many of the recent studies aimed at elucidating the mechanism of action of alcohols and general anesthetics have dealt with the effect of these agents on ligand-gated channels, whose ligand binding site is in a portion of the protein external to the bilayer (1, 7-10). The superfamily of G protein-coupled receptors has received relatively little study. In these receptors, the ligand binding sites are formed by their transmembrane helical segments and lie at the median point of the bilayer. One of the best characterized members of this superfamily is rhodopsin, which triggers the visual transduction pathway in rod cells. A metastable equilibrium between MI 1 and MII (whereis established within milliseconds of photon absorption (11). MII binds and activates the visual G protein, transducin (12, 13). MII formation increases with higher levels of phospholipid acyl chain u...

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Alcohol action on a neuronal membrane receptor: evidence for a direct interaction with the receptor protein.

Cited by 110 publications

References 22 publications

Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

Role of Altered Structure and Function of NMDA Receptors in Development of Alcohol Dependence

Alcohol inhibits cell-cell adhesion mediated by human L1 [published erratum appears in J Cell Biol 1996 Jun;133(5):1139-40]

Primary Alcohols Modulate the Activation of the G Protein-coupled Receptor Rhodopsin by a Lipid-mediated Mechanism

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