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First published on March 8, 2006; DOI: 10.1124/mol.105.021352

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Received for publication November 30, 2005.
Revised March 7, 2006.
Accepted for publication March 8, 2006.

Acute and chronic regulation of adenylyl cyclase activity by {delta}-opioid receptor are mediated by G{alpha}i2 in neuroblastoma N2A cells

Lei Zhang 1*, Joan Tetrault 1, Wei Wang 1, Horace H. Loh 1, Ping-Yee Law 2

1 University of Minnesota 2 Univesity of Minnesota Medical School

* Address correspondence to: E-mail: zhang247{at}umn.edu

Abstract

Activation of the opioid receptor results in acute inhibition of intracellular cAMP levels followed by receptor desensitization and subsequent increase of cAMP above the control level (adenylyl cyclase superactivation). Using adenovirus to deliver pertussis toxin insensitive mutants of the {alpha}-subunits of Gi/o that are expressed in neuroblastoma Neuro2A cells (G{alpha}i2, G{alpha}i3 and G{alpha}o), the identities of the G proteins involved in the acute and chronic action of the {delta}-opioid receptor (DOR) were examined. Pertussis toxin pretreatment abolished completely the ability of [D-Pen2, D-Pen5]-enkephalin (DPDPE) to inhibit forskolin-stimulated intracellular cAMP production. Expression of the C352L mutant of G{alpha}i2 and not the C351L mutants of G{alpha}i3 or G{alpha}o rescued the acute effect of DPDPE after pertussis toxin treatment. The ability of G{alpha}i2 in mediating DOR inhibition of adenylyl cyclase activity was also reflected in the ability of G{alpha}i2 and not G{alpha}i3 or G{alpha}o to co-immunoprecipitate with DOR. Coincidently, after chronic DPDPE treatment, pertussis toxin treatment eliminated the antagonist naloxone-induced superactivation of adenylyl cyclase activity. Again, only the C352L mutant of G{alpha}i2 restored the adenylyl cyclase superactivation after pertussis toxin treatment. More importantly, the C352L mutant of G{alpha}i2 remained associated with DOR after chronic agonist and pertussis toxin treatment while the wild type G{alpha}i2 did not. These data suggest that G{alpha}i2 serves as the signaling molecule in both DOR-mediated acute and chronic regulation of adenylyl cyclase activity.


Key words: Opioid, Gi family, cAMP, G protein regulation


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H. Zheng, J. Chu, Y. Qiu, H. H. Loh, and P.-Y. Law
Agonist-selective signaling is determined by the receptor location within the membrane domains
PNAS, July 8, 2008; 105(27): 9421 - 9426.
[Abstract] [Full Text] [PDF]


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