High-throughput sequence identification of gene coding variants within alcohol-related QTLs

Ehringer, Marissa A.; Thompson, Jessica A.; Conroy, Otakuye; Xu, Yan; Yang, Fan; Canniff, Jennifer; Beeson, Mary; Gordon, Lena; Bennett, Beth; Johnson, Thomas E.; Sikela, James M.

doi:10.1007/s00335-001-1001-x

Cited by 35 publications

(39 citation statements)

References 27 publications

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“…Because ethanol LORR is mediated by multiple molecular mechanisms, it is likely that distinct molecular mechanisms are responsible for hypnotic effect of different doses of ethanol. For example, at least four quantitative trait loci on different mouse chromosomes and 23 candidate genes have been identified, which are largely responsible for the heritable component of hypnotic sensitivity to ethanol in selected ILS and ISS strains of mice (Markel et al, 1997;Bennett and Johnson, 1998;Ehringer et al, 2001;MacLaren et al, 2006). Furthermore, genotypic differences in duration of ethanol-induced LORR can reflect differences in sensitivity, acute tolerance or ethanol clearance (Radcliffe et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Role of Endocannabinoids in Alcohol Consumption and Intoxication: Studies of Mice Lacking Fatty Acid Amide Hydrolase

Blednov¹,

Cravatt

Boehm

et al. 2006

Neuropsychopharmacol

123

103

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Endocannabinoid signaling plays the important role in regulation of ethanol intake. Fatty acid amide hydrolase (FAAH) is a key membrane protein for metabolism of endocannabinoids, including anandamide, and blockade of FAAH increases the level of anandamide in the brain. To determine if FAAH regulates ethanol consumption, we studied mutant mice with deletion of the FAAH gene. Null mutant mice showed higher preference for alcohol and voluntarily consumed more alcohol than wild-type littermates. There was no significant difference in consumption of sweet or bitter solutions. To determine the specificity of FAAH for ethanol intake, we studied additional ethanol-related behaviors. There were no differences between null mutant and wild-type mice in severity of ethanol-induced acute withdrawal, conditioned taste aversion to alcohol, conditioned place preference, or sensitivity to hypnotic effect of ethanol. However, null mutant mice showed shorter duration of loss of righting reflex induced by low doses of ethanol (3.2 and 3.4 g/kg) and faster recovery from motor incoordination induced by ethanol. All three behavioral phenotypes (increased preference for ethanol, decreased sensitivity to ethanol-induced sedation, and faster recovery from ethanol-induced motor incoordination) seen in mutant mice were reproduced in wild-type mice by injection of a specific inhibitor of FAAH activityFURB597. These data suggest that increased endocannabinoid signaling increased ethanol consumption owing to decreased acute ethanol intoxication.

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Section: Discussionmentioning

confidence: 99%

Role of Endocannabinoids in Alcohol Consumption and Intoxication: Studies of Mice Lacking Fatty Acid Amide Hydrolase

Blednov¹,

Cravatt

Boehm

et al. 2006

Neuropsychopharmacol

123

103

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“…Differentiated NT2-N cells with retinoic acid exhibited expression of KCC2, corroborating the presence of this transcript in a neuronal-derived cell line. KCC2 cDNA has been also isolated and sequenced from mouse by means of a highthroughput sequence study designed to identify gene-coding variants within alcohol-related QTLs in a mouse model of alcohol addiction (102) and also by the Mammalian Gene Collection Program Team (http//mgc.nci.nih.gov) (391).…”

Section: The Kmentioning

confidence: 99%

Molecular Physiology and Pathophysiology of Electroneutral Cation-Chloride Cotransporters

Gamba

2005

Physiological Reviews

697

754

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Electroneutral cation-Cl−cotransporters compose a family of solute carriers in which cation (Na+or K+) movement through the plasma membrane is always accompanied by Cl−in a 1:1 stoichiometry. Seven well-characterized members include one gene encoding the thiazide-sensitive Na+−Cl−cotransporter, two genes encoding loop diuretic-sensitive Na+−K+−2Cl−cotransporters, and four genes encoding K+−Cl−cotransporters. These membrane proteins are involved in several physiological activities including transepithelial ion absorption and secretion, cell volume regulation, and setting intracellular Cl−concentration below or above its electrochemical potential equilibrium. In addition, members of this family play an important role in cardiovascular and neuronal pharmacology and pathophysiology. Some of these cotransporters serve as targets for loop diuretics and thiazide-type diuretics, which are among the most commonly prescribed drugs in the world, and inactivating mutations of three members of the family cause inherited diseases such as Bartter's, Gitelman's, and Anderman's diseases. Major advances have been made in the past decade as consequences of molecular identification of all members in this family. This work is a comprehensive review of the knowledge that has evolved in this area and includes molecular biology of each gene, functional properties of identified cotransporters, structure-function relationships, and physiological and pathophysiological roles of each cotransporter.

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“…Preparation of PCR products from Creb1 cDNA was performed as described by Ehringer et al (2001). Briefly, C57 and DBA mice were sacrificed by cervical dislocation, and cerebellum was isolated and immediately frozen on liquid nitrogen.…”

Section: Qtls For Ethanol Sensitivity and Camp Signaling 1239mentioning

confidence: 99%

“…PCR products were sequenced directly as described by Ehringer et al (2001), using the ABI Prism Big Dye Terminator Sequencing Ready Reaction Kit (Applied Biosystems, Foster City, CA). Sequencing reactions were carried out as follows: 35 cycles of 10 s at 96°C, 50 s at 50°C, and 4 min at 60°C.…”

Section: Qtls For Ethanol Sensitivity and Camp Signaling 1239mentioning

confidence: 99%

Quantitative Trait Loci Affecting Initial Sensitivity and Acute Functional Tolerance to Ethanol-Induced Ataxia and Brain cAMP Signaling in BXD Recombinant Inbred Mice

Kirstein

Davidson²,

Ehringer³

et al. 2002

J Pharmacol Exp Ther

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In previous work, we identified genetic correlations between cAMP accumulation in the cerebellum and sensitivity to the incoordinating effects of ethanol. A genetic correlation suggests that common genes underlie the phenotypes investigated. One method for provisionally identifying genes involved in a given phenotypic measure is quantitative trait locus (QTL) analysis. Using a panel of 30 BXD recombinant inbred strains of mice and the progenitors (DBA/2J and C57BL/6J), and the dowel test for ataxia, we measured the blood ethanol concentrations at the time an animal first fell from the dowel and acute functional tolerance (AFT), and investigated cAMP signaling in the cerebellum. Cyclic AMP accumulation was measured in whole-cell preparations of cerebellar minces from individual mice under basal or stimulated conditions. We conducted a genome-wide QTL analysis of the behavioral and biochemical measures with Ͼ2000 genetic markers to identify significant associations. Western blot and comparative sequencing analysis were used to compare cAMP response element binding protein (CREB) levels and protein-coding sequence, respectively. QTL analyses correlating strain means with allelic status at genetic markers identified several significant associations (p Ͻ 0.01). Analysis of variance revealed an effect of strain on behavioral and biochemical measures. There was a significant genetic correlation between initial sensitivity and basal cAMP accumulation in the cerebellum. We identified 6 provisional QTLs for initial sensitivity on four chromosomes, 6 provisional QTLs for AFT on four chromosomes, and 11 provisional QTLs for cAMP signaling on nine chromosomes. Two loci were found to overlap for measures of initial sensitivity and for cAMP signaling. Given the genetic correlation between initial sensitivity and basal cAMP accumulation, we investigated candidate genes in a QTL on chromosome 1. Comparative sequence analysis was performed, and protein levels were compared between C57 and DBA mice for Creb1. No significant differences were detected in coding sequence or protein levels for CREB. These results suggest that although ethanol sensitivity and cAMP signaling are determined by multiple genes, they may share certain genetic codetermination.

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High-throughput sequence identification of gene coding variants within alcohol-related QTLs

Cited by 35 publications

References 27 publications

Role of Endocannabinoids in Alcohol Consumption and Intoxication: Studies of Mice Lacking Fatty Acid Amide Hydrolase

Role of Endocannabinoids in Alcohol Consumption and Intoxication: Studies of Mice Lacking Fatty Acid Amide Hydrolase

Molecular Physiology and Pathophysiology of Electroneutral Cation-Chloride Cotransporters

Quantitative Trait Loci Affecting Initial Sensitivity and Acute Functional Tolerance to Ethanol-Induced Ataxia and Brain cAMP Signaling in BXD Recombinant Inbred Mice

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