Psychiatry related information on Ppp1r1b

• Recent investigations have shown that three major striatal-signaling pathways (protein kinase A/DARPP-32, Akt/glycogen synthase kinase 3, and ERK) are involved in the regulation of locomotor activity by the monoaminergic neurotransmitter dopamine [1].
• This does not appear to be due to a learning deficit because mice lacking both DARPP-32 and I-1 show normal passive avoidance learning [2].
• DARPP-32 knockout mice exhibit impaired reversal learning in a discriminated operant task [3].
• However, significant differences in discrimination learning were observed during the reversal phase, with DARPP-32 knockout mice requiring significantly more trials to reach criterion than wild-type controls [3].
• Initially, wild-type and DARPP-32 knockout mice were trained to nose-poke for food on a continuous reinforcement schedule [3].

High impact information on Ppp1r1b

• Here we show that the stimulatory effect of caffeine on motor activity in mice was greatly reduced following genetic deletion of DARPP-32 (dopamine- and cyclic AMP-regulated phosphoprotein of relative molecular mass 32,000) [4].
• In support of a role for DARPP-32 in the action of caffeine, we found that, in striata of intact mice, caffeine increased the state of phosphorylation of DARPP-32 at Thr 75 [4].
• The depressant effect of the A(2A) receptor agonist, CGS 21680, on motor activity was also greatly attenuated in DARPP-32 knockout mice [4].
• Involvement of DARPP-32 phosphorylation in the stimulant action of caffeine [4].
• DARPP-32, a dopamine- and adenosine 3',5'-monophosphate (cAMP)-regulated phosphoprotein (32 kilodaltons in size), is an obligate intermediate in progesterone (P)-facilitated sexual receptivity in female rats and mice [5].

Chemical compound and disease context of Ppp1r1b

• We show here that mutation of Thr-34 in DARPP-32 mimicked the behavioral phenotype of the constitutive DARPP-32 knockout in cocaine-induced place conditioning, locomotor activity, and sensitization paradigms [6].
• N-Acetylaspartate and DARPP-32 levels decrease in the corpus striatum of Huntington's disease mice [7].

Biological context of Ppp1r1b

• Under basal conditions, dopamine transporter knock-out mice show enhanced striatal DARPP-32 phosphorylation, activation of ERK, and inactivation of Akt as compared with wild-type littermates [1].
• A full D(1) receptor agonist, SKF 82958, up-regulated the expression of these neuropeptides and immediate early genes significantly more in wild-type mice than in mice lacking DARPP-32 [8].
• These results demonstrate an important involvement of DARPP-32 in dopamine receptor-mediated regulation of gene expression both in striatal neurons, which are enriched in DARPP-32, and in pallidal neurons, which do not contain DARPP-32 [8].
• The effects of d-amphetamine or cocaine on ERK activation in the striatum, but not in the prefrontal cortex, were prevented by point mutation of Thr-34, a DARPP-32 residue specifically involved in protein phosphatase-1 inhibition [9].
• Mean arterial blood pressure, measured in conscious animals, was significantly increased in DARPP-32 deficient mice as compared to wild type mice [10].

Anatomical context of Ppp1r1b

• The role of the dopamine- and cyclic AMP-regulated phosphoprotein of M(r) 32,000 (DARPP-32) in dopaminergic regulation of gene transcription in striatum and globus pallidus was examined [8].
• DARPP-32 and inhibitor-1 are expressed in pancreatic beta-cells [11].
• P also enhanced phosphorylation of DARPP-32 on threonine 34 in the hypothalamus of mice [5].
• DARPP-32 and regulation of the ethanol sensitivity of NMDA receptors in the nucleus accumbens [12].
• We propose that DARPP-32 mediated blunting of the response to ethanol subsequent to activation of ventral tegmental area dopaminergic neurons initiates molecular alterations that influence synaptic plasticity in this circuit, thereby promoting the development of ethanol reinforcement [12].

Associations of Ppp1r1b with chemical compounds

• In contrast, conditioned place preference to cocaine is reduced in mice lacking DARPP-32, I-1, or both phosphoproteins [2].
• Requirement for DARPP-32 in progesterone-facilitated sexual receptivity in female rats and mice [5].
• DARPP-32 activation is thus an obligatory step in progestin receptor regulation of sexual receptivity in rats and mice [5].
• The regulation of ethanol sensitivity of NMDA receptors by D1 receptors was absent in DARPP-32 knockout mice [12].
• Glutamate regulation of DARPP-32 phosphorylation in neostriatal neurons involves activation of multiple signaling cascades [13].
• We demonstrated that both the PI3K/Akt/mammalian target of rapamycin and the cdk5/p35 signal transduction pathways contribute to the induction of DARPP-32 protein levels by BDNF and that the effects are on both the transcriptional and translational levels [14].

Enzymatic interactions of Ppp1r1b

• However, the absence of normal DA tone generated significant alterations in DA D1-receptor signalling as indicated by increased mutant striatal levels of phosphorylated DARPP-32 and by an altered motor response to amphetamine [15].
• DARPP-32 is also phosphorylated by cyclin-dependent kinase 5 on Thr75, and the phosphorylated form of DARPP-32 at Thr75 inhibits protein kinase (PKA) activity [16].

Regulatory relationships of Ppp1r1b

• We have recently reported that neurotensin stimulates the phosphorylation of DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of Mr 32 kDa) at Thr34 (PKA-site) by activating dopamine D1-type receptors in neostriatal neurons [16].
• These data show that DARPP-32 is involved in regulating substance P expression in the striatonigral pathway, and in biochemical and behavioural plasticity with chronic administration of cocaine [17].
• The effects of dopamine and psychostimulants on the phosphorylation of GluR1 were attenuated in dopamine and cAMP-regulated phosphoprotein M(r) 32 kDa (DARPP-32) knock-out mice [18].
• Recently it was shown that Cdk5 modulates dopamine signaling in neurons by regulating DARPP-32 function [19].
• In mouse neostriatal slices, the effect of DHPG on phosphorylation of Ser-137 or Thr-75 of DARPP-32 was blocked by the phospholipase Cbeta inhibitor, the Ca(2+) chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA/AM), and the calcineurin inhibitor cyclosporin A [20].

Other interactions of Ppp1r1b

• The Pax6;Gsh2 double mutants possess a larger striatum than the Gsh2 mutants, but the disproportionate reduction in DARPP-32 neurons is not improved [21].
• In this study, we examined the effect of neurotensin on DARPP-32 Thr75 phosphorylation using mouse neostriatal slices [16].
• The antipsychotic drug raclopride, a selective D2 receptor antagonist, increased phosphorylation of DARPP-32 under basal conditions and in D2 agonist-treated slices [22].
• The D1 receptor agonist SKF82526 increased DARPP-32 phosphorylation [22].
• We tested the hypothesis that the AMPA/KA or NMDA-stimulated dephosphorylation of DARPP-32 via calcineurin, leading to increased PP1 activity and dephosphorylation of GluR1 [23].

Analytical, diagnostic and therapeutic context of Ppp1r1b

• RT-PCR, Western blotting, and immunohistochemistry showed that DARPP-32 and inhibitor-1 are present in insulin-secreting endocrine beta-cells [11].
• The phosphorylation of DARPP-32 at threonine34 and threonine75 were examined using Western blotting [24].
• DARPP-32 (dopamine- and adenosine 3',5'-monophosphate-regulated phosphoprotein of Mr = 32,000) mRNA distribution was examined in adult mouse central nervous system by in situ hybridization [25].
• Notably, levels of P-Thr34- and P-Ser130-DARPP-32 were reduced after self-administration of cocaine in wild-type mice [26].
• Southern blot analysis of total bovine genomic DNA showed that there is a single gene coding for DARPP-32 [27].

References