Adenylyl cyclases types 1 and 8 promote pro-survival pathways after ethanol exposure in the neonatal brain.
Although a wide range of developmental disabilities following fetal alcohol exposure are observed clinically, the molecular factors that determine the severity of these sequelae remain undefined. In mice exposed to ethanol, deletion of adenylyl cyclases (ACs) 1 and 8 exacerbates the neuroapoptosis that occurs in a prolonged post-treatment period; however, it remains unclear whether AC1 and AC8 are critical to the primary or secondary mechanisms underlying ethanol-induced neurodegeneration. Here we demonstrate that mice lacking AC1 and AC8 (DKO) display significantly increased apoptosis in the striatum, a region sensitive to neuroapoptosis in the acute post-treatment period, compared to WT controls. The enhanced neuroapoptotic response observed in the striatum of DKO mice is accompanied by significant reductions in phosphorylation of known pro-survival proteins, insulin receptor substrate-1 (IRS-1), Akt and extracellular signal-regulated kinases (ERKs). These data suggest that AC1/AC8 are crucial activators of cell survival signaling pathways acutely following ethanol exposure and represent molecular factors that may directly modulate the severity of symptoms associated with Fetal Alcohol Syndrome.
Conti
Alana C
AC
Department of Pediatrics, Washington University in St. Louis, St. Louis, MO 63110, USA. conti_a@kids.wustl.edu
Young
Chainllie
C
Olney
John W
JW
Muglia
Louis J
LJ
D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival; D003342:Corpus Striatum / Q000166:cytology / Q000254:growth & development / Q000502:physiology*; D000431:Ethanol / Q000633:toxicity*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000378:metabolism / Q000503:physiopathology*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000502:physiology; D010766:Phosphorylation; D011247:Pregnancy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D000431:Ethanol; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D000262:Adenylyl Cyclases; C106670:adenylyl cyclase 1; C118292:adenylyl cyclase 8