Calcium-stimulated adenylyl cyclases are critical modulators of neuronal ethanol sensitivity.
The importance of the cAMP signaling pathway in the modulation of ethanol sensitivity has been suggested by studies in organisms from Drosophila melanogaster to man. However, the involvement of specific isoforms of adenylyl cyclase (AC), the molecule that converts ATP to cAMP, has not been systemically determined in vivo. Because AC1 and AC8 are the only AC isoforms stimulated by calcium, and ethanol modulates calcium flux by the NMDA receptor, we hypothesized that these ACs would be important in the neural response to ethanol. AC1 knock-out (KO) mice and double knock-out (DKO) mice with genetic deletion of both AC1 and AC8 display substantially increased sensitivity to ethanol-induced sedation compared with wild-type (WT) mice, whereas AC8 KO mice are only minimally more sensitive. In contrast, AC8 KO and DKO mice, but not AC1 KO mice, demonstrate decreased voluntary ethanol consumption compared with WT mice. DKO mice do not display increased sleep time compared with WT mice after administration of ketamine or pentobarbital, indicating that the mechanism of enhanced ethanol sensitivity in these mice is likely distinct from the antagonism of ethanol of the NMDA receptor and potentiation of the GABA(A) receptor. Ethanol does not enhance calcium-stimulated AC activity, but the ethanol-induced phosphorylation of a discrete subset of protein kinase A (PKA) substrates is compromised in the brains of DKO mice. These results indicate that the unique activation of PKA signaling mediated by the calcium-stimulated ACs is an important component of the neuronal response to ethanol.
Maas
James W
JW
Department of Pediatrics and Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Vogt
Sherri K
SK
Chan
Guy C K
GC
Pineda
Victor V
VV
Storm
Daniel R
DR
Muglia
Louis J
LJ
D000262:Adenylyl Cyclases / Q000172:deficiency / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001259:Ataxia / Q000503:physiopathology; D001522:Behavior, Animal; D015153:Blotting, Western / Q000379:methods; D002118:Calcium / Q000494:pharmacology*; D002492:Central Nervous System Depressants / Q000097:blood / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D000431:Ethanol / Q000097:blood / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005518:Food Preferences / Q000187:drug effects; D018755:GABA Agonists / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D007649:Ketamine / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D010424:Pentobarbital / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology; D011803:Quinine / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects; D012018:Reflex / Q000187:drug effects; D012439:Saccharin / Q000494:pharmacology; D012890:Sleep / Q000187:drug effects / Q000235:genetics
D002492:Central Nervous System Depressants; D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists; D007555:Isoxazoles; D000431:Ethanol; D007649:Ketamine; D016291:Dizocilpine Maleate; D011803:Quinine; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; C106670:adenylyl cyclase 1; C118292:adenylyl cyclase 8; D012439:Saccharin; D010424:Pentobarbital; C015542:gaboxadol; D002118:Calcium