Up-Regulation of AGS3 during Morphine Withdrawal Promotes cAMP Superactivation via Adenylyl Cyclase 5 and 7 in Rat Nucleus Accumbens/Striatal Neurons

Abstract

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␣ i -GDP to promote free G␤␥ stimulation of adenylyl cyclase (AC) 2 and 4, and/or inactivate G␣ 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␤␥. Instead, adenosine A2A receptor activation of G␣ s/olf seems to initiate cAMP superactivation and promote AGS3 up-regulation. Elevated AGS3 binds to G␣ i to prevent its inhibition on AC activation. Moreover, withdrawal-induced increases in cAMP/PKA activate phospholipase C and 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.

Phosphorylation of the N-methyl-d-aspartate receptor is increased in the nucleus accumbens during both acute and extended morphine withdrawal

“…This is a well-supported effect found both in culture (Chartoff et al, 2003;Fan et al, 2009) and in brain regions like the accumbens, amygdala, hippocampus, striatum, and prefrontal cortex (Edwards et al, 2009). Our finding of PKA activity being responsible for NMDA receptor changes during withdrawal fits well into this model of cellular change after opioid exposure, because PKA activation of NR1 increases the surface expression of the NMDA receptor .…”

“…One well-characterized aspect of opioid withdrawal is the hyperexcitability of mu opioid receptor containing cells during withdrawal (Chartoff et al, 2003;Fan et al, 2009;Edwards et al, 2009;Yang and Pu, 2009). This effect involves 39-59-cyclic adenosine monophosphate (cAMP) superactivation (Chartoff et al, 2003;Fan et al, 2009;Edwards et al, 2009;Yang and Pu, 2009).…”

“…This effect involves 39-59-cyclic adenosine monophosphate (cAMP) superactivation (Chartoff et al, 2003;Fan et al, 2009;Edwards et al, 2009;Yang and Pu, 2009). The changes in neuronal activity, cAMP, and cAMP-dependent protein kinase A (PKA) activation produced by withdrawal could modulate NMDA receptors (Fan et al, 2009;Anderson et al, 2012a,b) because its NR1 subunit can be phosphorylated on serine 897 (pNR1) by PKA (Tingley et al, 1997). Changes in the expression of pNR1 were previously reported in animal models of pain (Caudle et al, 2003;Zhou et al, 2006) as well as ethanol (Ferrani-Kile et al, 2003) and cocaine abuse (Scheggi et al, 2007).…”

Distribution of Activator of G-Protein Signaling 3 within the Aggresomal Pathway: Role of Specific Residues in the Tetratricopeptide Repeat Domain and Differential Regulation by the AGS3 Binding Partners Giα and Mammalian Inscuteable

“…AGS3 is involved in a number of different cellular activities, including asymmetric cell division during neuronal development (30), neuronal plasticity and addiction (9,10,12,38,39), autophagy (27), membrane protein trafficking (17), cardiovascular function (7), and metabolism (7). AGS3 is a multidomain protein consisting of seven tetratricopeptide repeats (TPR) in the amino-terminal portion of the protein and four G-protein regulatory (GPR) motifs in the carboxyl region of the protein.…”

Activators of G Protein Signaling in the Kidney

“…Gbg activity has been implicated in mitotic spindle orientation (Sanada and Tsai, 2005), ion channel activity (Kwon et al, 2012), cAMP production (Fan et al, 2009), or modulation of GPCR-dependent Oner et al, 2010Oner et al, , 2013 and GPCR-independent signaling pathways (Smrcka, 2008;Smrcka et al, 2008;Lin and Smrcka, 2011). Overexpression of AGS3/GPSM1 facilitated an increase of polycystin-1/-2 ion channel activity, which could be blocked by a scavenger of Gbg dimers (Kwon et al, 2012).…”