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PMID:19571131

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Citation

Peng, J, Wagle, M, Mueller, T, Mathur, P, Lockwood, BL, Bretaud, S and Guo, S (2009) Ethanol-modulated camouflage response screen in zebrafish uncovers a novel role for cAMP and extracellular signal-regulated kinase signaling in behavioral sensitivity to ethanol. J. Neurosci. 29:8408-18

Abstract

Ethanol, a widely abused substance, elicits evolutionarily conserved behavioral responses in a concentration-dependent manner in vivo. The molecular mechanisms underlying such behavioral sensitivity to ethanol are poorly understood. While locomotor-based behavioral genetic screening is successful in identifying genes in invertebrate models, such complex behavior-based screening has proven difficult for recovering genes in vertebrates. Here we report a novel and tractable ethanol response in zebrafish. Using this ethanol-modulated camouflage response as a screening assay, we have identified a zebrafish mutant named fantasma (fan), which displays reduced behavioral sensitivity to ethanol. Positional cloning reveals that fan encodes type 5 adenylyl cyclase (AC5). fan/ac5 is required to maintain the phosphorylation of extracellular signal-regulated kinase (ERK) in the forebrain structures, including the telencephalon and hypothalamus. Partial inhibition of phosphorylation of ERK in wild-type zebrafish mimics the reduction in sensitivity to stimulatory effects of ethanol observed in the fan mutant, whereas, strikingly, strong inhibition of phosphorylation of ERK renders a stimulatory dose of ethanol sedating. Since previous studies in Drosophila and mice show a role of cAMP signaling in suppressing behavioral sensitivity to ethanol, our findings reveal a novel, isoform-specific role of AC signaling in promoting ethanol sensitivity, and suggest that the phosphorylation level of the downstream effector ERK is a critical "gatekeeper" of behavioral sensitivity to ethanol.

Links

PubMed PMC2722107 Online version:10.1523/JNEUROSCI.0714-09.2009

Keywords

Adenylate Cyclase/genetics; Adenylate Cyclase/metabolism; Adrenocorticotropic Hormone/metabolism; Analysis of Variance; Animals; Animals, Genetically Modified; Behavior, Animal/drug effects; Behavior, Animal/physiology; Brain/anatomy & histology; Brain/drug effects; Brain/growth & development; Brain/metabolism; Central Nervous System Depressants/pharmacology; Chromosome Mapping/methods; Cyclic AMP/genetics; Cyclic AMP/metabolism; Darkness; Dose-Response Relationship, Drug; Ethanol/pharmacology; Extracellular Signal-Regulated MAP Kinases/genetics; Extracellular Signal-Regulated MAP Kinases/metabolism; Gene Expression Regulation, Developmental/drug effects; Gene Expression Regulation, Developmental/genetics; Green Fluorescent Proteins/genetics; Hu Paraneoplastic Encephalomyelitis Antigens/metabolism; Isoenzymes/genetics; Isoenzymes/metabolism; Larva; Light; Locomotion/drug effects; Locomotion/genetics; Melanosomes/drug effects; Mutation/genetics; Phosphorylation/drug effects; Reaction Time/drug effects; Signal Transduction/drug effects; Signal Transduction/genetics; Spatial Behavior/drug effects; Spatial Behavior/physiology; Zebrafish/genetics; Zebrafish/physiology

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DANRE:A0A2R8QEV2

involved_in

GO:0045471: response to ethanol

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-090806-5

P

Seeded From UniProt

complete

DANRE:A0A2R8QEV2

involved_in

GO:0001932: regulation of protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

DANRE:D2CFN3

involved_in

GO:0045471: response to ethanol

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-090806-5

P

Seeded From UniProt

complete

DANRE:D2CFN3

involved_in

GO:0001932: regulation of protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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