Up-regulation of AGS3 during morphine withdrawal promotes cAMP superactivation via adenylyl cyclase 5 and 7 in rat nucleus accumbens/striatal neurons.
Effective medical treatment of opiate addiction is limited by a high relapse rate in abstinent addicts. Opiate withdrawal causes cAMP superactivation, but the underlying molecular mechanisms are not clear. Recent evidence implicates an activator of G-protein signaling 3 (AGS3) in opiate addiction. We found previously that during a 10-min activation of opioid receptors, AGS3 binds G alpha(i)-GDP to promote free G betagamma stimulation of adenylyl cyclase (AC) 2 and 4, and/or inactivate G alpha(i) inhibitory function, thereby transiently enhancing cAMP-dependent protein kinase A (PKA) activity. In contrast, we report here that in nucleus accumbens/striatal neurons, morphine withdrawal induces cAMP superactivation, which requires up-regulation of AGS3. cAMP increases as a function of withdrawal time, by approximately 20% at 10 min and 75% at 5 h. However, cAMP superactivation does not require G betagamma. Instead, adenosine A2A receptor activation of G alpha(s/olf) seems to initiate cAMP superactivation and promote AGS3 up-regulation. Elevated AGS3 binds to G alpha(i) to prevent its inhibition on AC activation. Moreover, withdrawal-induced increases in cAMP/PKA activate phospholipase C and epsilon protein kinase C to further stimulate AC5 and AC7, causing cAMP superactivation. Our findings identify a critical role for AC 5 and 7 and A2A receptors for up-regulation of AGS3 in morphine withdrawal-induced cAMP superactivation.
Fan
Peidong
P
Gilead Sciences, Inc., 3172 Porter Drive, Palo Alto, California 94304, USA.
Jiang
Zhan
Z
Diamond
Ivan
I
Yao
Lina
L
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis*; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000201:enzymology*; D000242:Cyclic AMP / Q000819:agonists*; D007527:Isoenzymes / Q000378:metabolism*; D009020:Morphine / Q000008:administration & dosage*; D009474:Neurons / Q000201:enzymology; D009714:Nucleus Accumbens / Q000201:enzymology*; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*; D015854:Up-Regulation
D002352:Carrier Proteins; C498913:Gpsm1 protein, rat; D007527:Isoenzymes; D043705:Receptor, Adenosine A2A; D009020:Morphine; D000242:Cyclic AMP; D051744:Protein Kinase C-epsilon; D000262:Adenylyl Cyclases; C473265:adenylyl cyclase 7; C419510:adenylyl cyclase type V