DARPP-32 mediates the actions of multiple drugs of abuse

Abstract

A BSTRACTDrugs of abuse share the ability to enhance dopaminergic neurotransmission in the dorsal and ventral striatum. The action of dopamine is modulated by additional neurotransmitters, including glutamate, serotonin and adenosine. All these neurotransmitters regulate the phosphorylation state of Dopaminal serine/threonine protein phosphatase, PP-1. Phosphorylatine-and cAMP-regulated phosphoprotein, Mr 32 kDa . Phosphorylation at Thr 34 by protein kinase A converts DARPP-32 into a potent inhibitor of the multifunctioon at Thr 75 by Cdk5 converts DARPP-32 into an inhibitor of protein kinase A. The state of phosphorylation of DARPP-32 at Thr 34 also depends on the phosphorylation state of Ser 97 and Ser 130 , which are phosphorylated by CK2 and CK1, respectively. By virtue of regulation of these 4 phosphorylation sites, and through its ability to modulate the activity of PP-1 and protein kinase A, DARPP-32 plays a key role in integrating a variety of biochemical, electrophysiological, and behavioral responses controlled by dopamine and other neurotransmitters. Importantly, there is now a large body of evidence that supports a key role for DARPP-32-dependent signaling in mediating the actions of multiple drugs of abuse including cocaine, amphetamine, nicotine, caffeine, LSD, PCP, ethanol and morphine.K EYWORDS : protein phosphorylation, psychostimulants, dopamine, striatum DARPP-32, A MULTIFUNCTIONAL REGULATOR OF PROTEIN KINASES AND PROTEIN PHOSPHATASESDopamine-and cAMP-regulated phosphoprotein, Mr 32 kDa (DARPP-32), was initially discovered as a major target for dopamine-activated adenylyl cyclase and protein kinase A (PKA) in striatum. 1 Phosphorylation by PKA at Thr 34 converts DARPP-32 into a potent high-affi nity inhibitor of the multifunctional serine/threonine protein phosphatase, PP-1. The IC 50 for inhibition of PP-1 is ~10 − 9 M. 2 Since DARPP-32 is expressed in very high concentration (~50 m M) in all medium spiny neurons, 3 including those in both the striatonigral and striato pallidal projection pathways (see below), and the concentration of all PP-1 isoforms is likely less than 20 m M, 4 a substantial proportion of PP-1 activity will be inhibited in response to even moderate increases in DARPP-32 phosphorylation.Detailed structure-function studies have established that the fi rst 40 amino acids at the NH 2 -terminus of DARPP-32 are suffi cient (when Thr 34 is phosphorylated) for DARPP-32 to bind to and inhibit PP-1. Moreover, several different types of biochemical approaches have revealed that the remaining COOH-terminal portion of DARPP-32 serves an important role in the modulation of DARPP-32 function. In intact neurons, DARPP-32 is highly phosphorylated at Ser 97 and Ser 130 under basal conditions. Ser 97 is phosphorylated by CK2 and Ser 130 is phosphorylated by CK1. In vitro, phosphorylation of Ser 97 of DARPP-32 increases the effi ciency of phosphorylation of Thr 34 by PKA. 5 In vitro, phosphorylation of Ser 130 decreases the rate of dephosphorylation of Thr 34 by PP-2B, 6 and in striatal slic...

Administration of the calcineurin inhibitor cyclosporine modulates cocaine-induced locomotor activity in rats

“…While phosphorylation of another calcineurin target protein, DARPP32, has also been implicated in cocaine-mediated behavior (Svenningsson et al 2005), repeated cocaine or cyclosporine administration did not alter DARPP32 phosphorylation in the present study. Although calcineurin inhibition has also been shown to increase DARPP-32 phosphorylation (Nishi et al 2002), these demonstrations have been performed in slices preparations that are isolated from the rest of the mesolimbic dopamine system.…”

“…Thus, the fact that repeated administration of cocaine or cyclosporine led to increased pSyn I (S62/67) suggests that synapsin I may be a molecular target of both drugs. While DARPP32 is another calcineurin target that has been shown to be regulated by cocaine exposure (Svenningsson et al 2005), examination of striatal tissue revealed no significant differences in levels of phosphorylated DARPP32 at a calcineurin sensitive site (threonine 34) after repeated cocaine or cyclosporine administration (data not shown).…”

Tissue plasminogen activator modulates the cellular and behavioral response to cocaine

“…The subsequent increase in intracellular cAMP levels and protein kinase A (PKA) activation results in initiation of intracellular signaling pathways (27). In the amygdala, activation of PKA leads to phosphorylation of ERK and activation of IEGs (28).…”

“…In the amygdala, activation of PKA leads to phosphorylation of ERK and activation of IEGs (28). Cocaine induces phosphorylation of DARPP-32 at Thr-34 in a subset of neurons in the NAc (27,28). This in turn leads to phosphorylation of the transcription factor CREB and its subsequent translocation to the nucleus where it initiates a program of gene expression (29).…”

Dopamine D1 vs D5 receptor-dependent induction of seizures in relation to DARPP-32, ERK1/2 and GluR1-AMPA signalling

“…Interestingly, the PLC-stimulating agonist SKF 83959 was found to inhibit DARPP-32 phosphorylation at Thr34 in the striatum, which may explain its lack of convulsant effect. Of note, Rashid and colleagues (2007) have recently reported that SKF 83959 stimulates PLC and intracellular calcium release by activating D 1 -D 2 heterooligomers where it is a full agonist at the D 1 receptor and a partial agonist at the D 2 receptor; D 2 receptor activation inhibits DARPP-32 phosphorylation at Thr34 and is known to be anticonvulsant (Bozzi et al, 2000;Svenningsson et al, 2004Svenningsson et al, , 2005.…”