Regulation of ethanol-related behavior and ethanol metabolism by the Corazonin neurons and Corazonin receptor in Drosophila melanogaster.
Impaired ethanol metabolism can lead to various alcohol-related health problems. Key enzymes in ethanol metabolism are alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH); however, neuroendocrine pathways that regulate the activities of these enzymes are largely unexplored. Here we identified a neuroendocrine system involving Corazonin (Crz) neuropeptide and its receptor (CrzR) as important physiological regulators of ethanol metabolism in Drosophila. Crz-cell deficient (Crz-CD) flies displayed significantly delayed recovery from ethanol-induced sedation that we refer to as hangover-like phenotype. Newly generated mutant lacking Crz Receptor (CrzR(01) ) and CrzR-knockdown flies showed even more severe hangover-like phenotype, which is causally associated with fast accumulation of acetaldehyde in the CrzR(01) mutant following ethanol exposure. Higher levels of acetaldehyde are likely due to 30% reduced ALDH activity in the mutants. Moreover, increased ADH activity was found in the CrzR(01) mutant, but not in the Crz-CD flies. Quantitative RT-PCR revealed transcriptional upregulation of Adh gene in the CrzR(01) . Transgenic inhibition of cyclic AMP-dependent protein kinase (PKA) also results in significantly increased ADH activity and Adh mRNA levels, indicating PKA-dependent transcriptional regulation of Adh by CrzR. Furthermore, inhibition of PKA or cAMP response element binding protein (CREB) in CrzR cells leads to comparable hangover-like phenotype to the CrzR(01) mutant. These findings suggest that CrzR-associated signaling pathway is critical for ethanol detoxification via Crz-dependent regulation of ALDH activity and Crz-independent transcriptional regulation of ADH. Our study provides new insights into the neuroendocrine-associated ethanol-related behavior and metabolism.
Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee, United States of America.
Kai
K
Sha
Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee, United States of America.
Seung-Hoon
SH
Choi
Department of Microbiology, University of Tennessee, Knoxville, Tennessee, United States of America.
Jeongdae
J
Im
Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee, United States of America.
Gyunghee G
GG
Lee
Department of Microbiology, University of Tennessee, Knoxville, Tennessee, United States of America.
Frank
F
Loeffler
Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee, United States of America ; Genome Science Technology, University of Tennessee, Knoxville, Tennessee, United States of America.
Jae H
JH
Park
D000079:Acetaldehyde / Q000378:metabolism; D000426:Alcohol Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000483:Alleles; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D000431:Ethanol / Q000378:metabolism* / Q000494:pharmacology; D017930:Genes, Reporter; D008297:Male; D009154:Mutation / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000378:metabolism*; D014158:Transcription, Genetic
C489221:Crz protein, Drosophila; D029721:Drosophila Proteins; D009479:Neuropeptides; D012333:RNA, Messenger; D018013:Receptors, Neuropeptide; C468120:corazonin receptor; D000431:Ethanol; D000426:Alcohol Dehydrogenase; D000444:Aldehyde Dehydrogenase; D017868:Cyclic AMP-Dependent Protein Kinases; D000079:Acetaldehyde