QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

The Journal of Neuroscience, April 20, 2005, 25(16):4118-4126; doi:10.1523/JNEUROSCI.4273-04.2005

This Article Full Text Full Text (PDF) Supplemental Material Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (22) Citing Articles via Google Scholar Google Scholar Articles by Maas, J. W. Articles by Muglia, L. J. Search for Related Content PubMed PubMed Citation Articles by Maas, J. W., Jr Articles by Muglia, L. J.

 Previous Article  |  Next Article 

Behavioral/Systems/Cognitive
Calcium-Stimulated Adenylyl Cyclases Are Critical Modulators of Neuronal Ethanol Sensitivity

James W. Maas, Jr,¹ Sherri K. Vogt,¹ Guy C. K. Chan,² Victor V. Pineda,² Daniel R. Storm,² and Louis J. Muglia¹

¹Department of Pediatrics and Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, Missouri 63110, and ²Department of Pharmacology, The University of Washington, Seattle, Washington 98195

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.

Key words: adenylyl cyclase; calcium; cAMP; ethanol; knock-out mouse; pharmacology; protein kinase A

---

Received March 24, 2004; revised March 13, 2005; accepted March 13, 2005.

This article has been cited by other articles:

				J. Peng, M. Wagle, T. Mueller, P. Mathur, B. L. Lockwood, S. Bretaud, and S. Guo 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., July 1, 2009; 29(26): 8408 - 8418. [Abstract] [Full Text] [PDF]

				M. K. Kelm, H. E. Criswell, and G. R. Breese The Role of Protein Kinase A in the Ethanol-Induced Increase in Spontaneous GABA Release Onto Cerebellar Purkinje Neurons J Neurophysiol, December 1, 2008; 100(6): 3417 - 3428. [Abstract] [Full Text] [PDF]

				C. D'Addario, Y. Ming, S.-O. Ogren, and L. Terenius The role of acetaldehyde in mediating effects of alcohol on expression of endogenous opioid system genes in a neuroblastoma cell line FASEB J, March 1, 2008; 22(3): 662 - 670. [Abstract] [Full Text] [PDF]

				C.-C. Lai, T.-I. Kuo, and H.-H. Lin The Role of Protein Kinase A in Acute Ethanol-Induced Neurobehavioral Actions in Rats Anesth. Analg., July 1, 2007; 105(1): 89 - 96. [Abstract] [Full Text] [PDF]

				H. Wang, B. Gong, K. I. Vadakkan, H. Toyoda, B.-K. Kaang, and M. Zhuo Genetic Evidence for Adenylyl Cyclase 1 as a Target for Preventing Neuronal Excitotoxicity Mediated by N-Methyl-D-aspartate Receptors J. Biol. Chem., January 12, 2007; 282(2): 1507 - 1517. [Abstract] [Full Text] [PDF]

				I. Ragan Alcohol alternatives - a goal for psychopharmacology? J Psychopharmacol, May 1, 2006; 20(3): 325 - 326. [PDF]

				A. M. Vanhoose, J. M. Clements, and D. G. Winder Novel Blockade of Protein Kinase A-Mediated Phosphorylation of AMPA Receptors J. Neurosci., January 25, 2006; 26(4): 1138 - 1145. [Abstract] [Full Text] [PDF]

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help