Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

DARPP-32 (Ppp1r1b)

  • Daniela V. Rosa
  • Luiz Alexandre V. Magno
  • Bruno R. Souza
  • Marco A. Romano-Silva
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_557

Synonyms

Historical Background

Protein phosphorylation is one of the most important posttranslational events that regulate myriad of biological processes such as cell division, cell differentiation, metabolism and modulation of signal transduction pathways (Ubersax and Ferrell 2007).

Studies using behavioral analysis of animal models suggest that alterations in critical intracellular signaling pathways have an important role in the pathophysiology and treatment of complex neuropsychiatric disorders. The hypothesis is that if the vast majority of psychiatric medications exert their primary therapeutic actions in the first week of treatment, the therapeutic effects involve transcriptional changes initiated and maintained by critical intracellular signaling pathways.

The dopaminergic neurotransmission system has been the focus of much research throughout the last few decades, including psychiatric and neurological disorders, and drug action mechanisms. Dopamine is associated with motor behavior, pleasure and reward, cognition, among other functions. It is well known that dopamine plays a major role in the coordination and regulation of the two output pathways by acting in a bidirectional manner. Five different dopamine receptors were cloned in humans and classified into two subgroups: D1 and D2 receptors. Many electrophysiological and gene transcriptional data, obtained in vitro and in vivo, suggest that dopamine exerts stimulatory effects via D1 receptors and inhibitory effects via D2 receptors (West and Grace 2002). All of the dopaminergic receptors are metabotropic and alter cAMP signaling: D1 receptor subtypes (D1, D5) stimulate adenylyl cyclase, whereas D2 receptor subtypes (D2S, D2L, D3, D4) inhibit adenylyl cyclase (Svenningsson et al. 2004).

Initially discovered as the major target for dopamine-activated adenylyl cyclase and PKA in striatum, DARPP-32 (dopamine and cAMP-regulated phosphoprotein Mr 32,000), which is also called PPP1R1B (protein phosphatase 1 regulatory subunit 1B), is a hub for signaling by multiple receptors and its regulation has been modeled by several groups (Li et al. 2015) and has a central role in the biology of dopaminoceptive neurons in the central and peripheral nervous system (Reis et al. 2007). The phosphorylation by PKA at Thr34 converts DARPP-32 into a potent high-affinity inhibitor of the multifunctional serine/threonine protein phosphatase, PP-1 (Svenningsson et al. 2004), including several neurotransmitter receptors, ion channels, and transcription factors (Yamada et al. 2016).

DARPP-32 is also phosphorylated at Thr75 by Cdk5 converting DARPP-32 into an inhibitor of PKA. Furthermore, the state of phosphorylation of DARPP-32 at Thr34 is fine-tuned by the phosphorylation state of two serine residues, Ser102 and Ser137, which are phosphorylated by CK2 and CK1, respectively. Thus, by virtue of its unique ability to modulate the activity of both PP-1 and PKA, DARPP-32 is critically involved in regulating electrophysiological, transcriptional, and behavioral responses to physiological and pharmacological stimuli, including antidepressants, neuroleptics, and drugs of abuse (Svenningsson et al. 2004).

The serotonergic neurotransmitter system, together with the dopaminergic system, regulates emotion, mood, reward, and cognition. Detailed studies in striatal slices and whole animals have shown that serotonin causes an increase in phosphorylation of DARPP-32 at Thr34 and Ser137 and decreased phosphorylation at Thr75. The actions of serotonin in regulating phosphorylation of DARPP-32 at Thr34 and Thr75 were mediated primarily via activation of 5-HT4 and 5-HT6 receptors, whereas the regulation of phosphorylation at Ser137 was mediated primarily via 5-HT2 receptors. DARPP-32 phosphorylation is also modulated by glutamate, GABA, neuromodulators, and neuropeptides (Svenningsson et al. 2004).

In addition to the brain, DARPP-32 is expressed in the adrenal medulla, kidney, and parathyroid cells (Belkhiri et al. 2016), and beside its main role in dopamine signaling, other recent studies also revealed wide functions of DARPP-32 such as binding to tra2-beta1 in regulating alternative splicing events (Benderska et al. 2010). For instance, it has been reported that the truncated form of DARPP-32 (t-DARPP-32), where amino acid residues encoded by exon one are missing, is highly expressed in cancers (Belkhiri et al. 2008; Vangamudi et al. 2010). Thus, deregulated or loss of DARPP-32 activities can transform normal thyroid cells to tumors. Also, overexpression of DARPP-32 enhanced interactions between EGFR and ERBB3 and promoted tumor resistance to antitumor drug gefitinib via increased phosphorylation of AKT (Ung and Teoh 2014; Zhu et al. 2011) and frequent amplification of 17q12, the locus of DARPP-32, in gastric and esophageal adenocarcinomas (El-Rifai et al. 2002).

DARPP-32 Knockout and Mutant Mice

The generation of DARPP-32 knockout (KO) mice (Fienberg et al. 1998) and mutant mice with point mutations in phosphorylation sites of DARPP-32 (Svenningsson 2003) has provided a powerful tool for the search of the DARPP-32 roles in both behavioral and neurobiological basis of several diseases. Overall, studies have shown that DARPP-32 is required for the physiological actions of dopamine. A well-accepted molecular explanation for this role is the reduced induction of gene expression after treatment with D1 receptor agonists in mice lacking DARPP-32 (Svenningsson et al. 2000a).

Studies using DARPP-32 KO mice have indicated that DARPP-32-dependent pathways are involved in the modulation of the short, and perhaps long, term actions of drugs of abuse (Svenningsson et al. 2005). In fact, addictive properties of most drugs of abuse are mediated via dopaminergic pathways, particularly through postsynaptic neurons within the striatum, which contains high levels of DARPP-32. For example, cocaine preference (Zachariou et al. 2002), ethanol reward (Risinger et al. 2001), and stimulatory effects of caffeine on motor activity (Lindskog et al. 2002) are reduced in mice lacking DARPP-32. Also, hyperlocomotor response to D-methamphetamine in mice lacking PDE1B was blocked in PDE1B-DARPP-32 double-KO mice (Ehrman et al. 2006). Similar results were reported in Thr34 and Thr75 mutant mice, which denote that behavioral and biochemical actions of cocaine depend on phosphorylation sites of DARPP-32 (Zachariou et al. 2002).

Evidence has also shown a critical role for DARPP-32 in the therapeutic drug actions. The antidepressant effects of fluoxetine, a drug that increases phosphorylation of DARPP-32 at Thr34, was strongly reduced in DARPP-32 knockout mice (Lindskog et al. 2002). For more detailed information, see Fienberg and Greengard (2000).

DARPP-32 and Human Genetics

Since the function of DARPP-32 is endogenously regulated by the action of neurotransmitters and neuromodulators, and exogenously by cocaine and therapeutic drugs, genetic variations in the DARPP-32 gene (also known as PPP1R1B; located on 17q12) have been long viewed as potential biomarkers for psychiatric disorders. The initial evidence that a chromosomal region within 17q, which includes the PPP1R1B gene, increases the risk for schizophrenia (Cardno et al. 2001) and bipolar disorder (Dick et al. 2003), has offered a useful starting point for genetic studies. However, a few studies have examined the influence of variations in PPP1R1B gene on psychiatric symptoms.

To date, genetic association studies involving the PPP1R1B gene were performed in schizophrenia, bipolar disorder, autism, addiction, neurocognitive functions, attention-deficit hyperactivity disorder (ADHD), and breast cancer. Among them, positive associations were found only for nicotine dependence, autism and a miscellaneous of neurocognitive functions. Overall, weak-to-moderate associations were reported, and the inconsistent data can be partially explained by the genetic diversity of the populations studied and polymorphism discrepancy.

In a sample of 2037 subjects, Beuten et al. (2007) found that a PPP1R1B haplotype formed by the single nucleotide polymorphisms (SNPs) rs2271309, rs907094, rs3764352, and rs3817160 was significantly associated with smoking quantity in European-Americans, but not in African-Americans (Beuten et al. 2007). These data not only suggest that nicotine addiction risk is predisposed by PPP1R1B polymorphisms, but also that it appears to be influenced by ethnic diversity. Using a translational genetics approach, Meyer-lindenberg et al. (2007a) found that the same schizophrenia-related PPP1R1B variants that impact on cognitive functions also predicted the DARPP-32 mRNA expression. Interestingly, in an independent sample of healthy Caucasian subjects, these same polymorphisms were associated with different patterns of neostriatal morphology and function (Meyer-Lindenberg et al. 2007b).

In a cohort of 112 males with autism, Hettinger et al. (2012) found an increased frequency of CC genotype for the rs1495099 SNP in affected individuals. Authors also suggested this genotype is associated with severe problems of social interaction, communication, and increased stereotypic behaviors (Hettinger et al. 2012).

The rs907094 is by far the most studied PPP1R1B SNP. This polymorphism, which is associated with striatal dopamine function, has been shown to predict some neurocognitive functions such as human reinforcement learning (Frank et al. 2007), emotional learning (ĆurČić-Blake et al. 2012), the work memory (Schuck et al. 2013; Smith et al. 2014), auditory perception (Li et al. 2013), and brain-evoked potentials (Hämmerer et al. 2013). Knowledge of how genetic variations in the PPP1R1B such as rs907094 affect dopamine-dependent behaviors may have substantial implications for several psychiatric disorders.

Psychiatric Disorders and Neurological Diseases

Schizophrenia (SCZ): SCZ is a disease that affects 1% of the worldwide population. Abnormalities in the dopamine, glutamate, and GABA neurotransmitter systems are involved in the SCZ etiology (Chiapponi et al. 2016; Rowland et al. 2013; Souza et al. 2006). The DARPP-32 signaling pathway is regulated by these neurotransmitters’ signaling (Yger and Girault 2011). Several studies, using postmortem brain and lymphocytes from SCZ patients, have reported alterations in the DARPP-32 levels (see Table 1). These studies demonstrated a decrease in the protein levels, but not mRNA, in the dorsolateral prefrontal cortex of patients, a region suggested to be associated with negative symptoms and cognitive impairments of SCZ (Albert et al. 2002; Baracskay et al. 2006; Ishikawa et al. 2007; Kunii et al. 2014a). The number of DARPP-32 expressing neurons is diminished within the neurons of the layers II, III, IV, and V of SCZ dorsolateral prefrontal cortex, but there are no changes in the number of glia cells expressing DARPP-32 (Kunii et al. 2011a). On the other hand, the expression of t-DARPP-32 transcripts is increased in the dorsolateral prefrontal cortex of the patients (Kunii et al. 2014b). The decrease of DARPP-32 in this region was not affected by the age of patients (Albert et al. 2002; Ishikawa et al. 2007). It was also observed a reduction in the number of neurons and the number of DARPP-32 expressing neurons within the CA3 subregion of the hippocampus and in the layers III and IV of superior temporal gyrus cortex of SCZ (Kunii et al. 2011a; Kunii et al. 2011b). But there are no changes in the mRNA expression levels of both DARPP-32 and t-DARPP-32 within the hippocampus and caudate nucleus of patients (Kunii et al. 2014b). On the other hand, there is an increase in the number of neurons expressing DARPP-32 within the layer V of SCZ and expression of t-DARPP-32 in the striatum. Also, no alterations were demonstrated in the mRNA levels of DARPP-32 in the anterior cingulated cortex and thalamus of SCZ patients (Baracskay et al. 2006). Recently, levels of DARPP-32 were shown to be decreased in lymphocytes of SCZ patients, but not mRNA DARPP-32 levels, suggesting that DARPP-32 protein levels can be a potential biomarker for this illness (Torres et al. 2009) (see Table 1). Several studies showed that blocking D2 receptors, the main target of antipsychotics can increase the phosphorylation of DARPP-32(Thr34), affecting motor behavior (Yger and Girault 2011; Svenningsson et al. 2000b). This modulation is impaired in DARPP-32 KO mice (Fienberg and Greengard 2000; Heyser et al. 2000). However, antipsychotics do not regulate the expression of DARPP-32, suggesting that the decrease of DARRP-32 in the prefrontal cortex of SCZ patients is related to the disease and not to the pharmacological treatment (Baracskay et al. 2006; Souza et al. 2010; Feldcamp et al. 2008).
DARPP-32 (Ppp1r1b), Table 1

DARPP-32 and psychiatric and neurological disorders – summary of DARPP-32 expression patterns in samples from psychiatric and neurologic disorder patients

Disorder

Sample

DARPP-32 or

t-DARPP-32

Alterations

Major depression

Dorsolateral prefrontal cortex

DARPP-32

Increase: mRNA (Kunii et al. 2014a)

t-DARPP-32

Increase: mRNA (Kunii et al. 2014b)

Hippocampus

DARPP-32

No alterations: mRNA (Kunii et al. 2014a)

t-DARPP-32

No Alterations: mRNA (Kunii et al. 2014b)

Schizophrenia

Dorsolateral prefrontal cortex

DARPP-32

Decrease: protein (Albert et al. 2002; Ishikawa et al. 2007; Kunii et al. 2011b); mRNA in suicidal patients (Feldcamp et al. 2008)

No alterations: mRNA (Baracskay et al. 2006)

t-DARPP-32

Increase: mRNA (Kunii et al. 2014a)

Hippocampus

DARPP-32

Decrease: protein (Kunii et al. 2011a)

No alterations: mRNA (Kunii et al. 2014b)

t-DARPP-32

No alterations: mRNA (Kunii et al. 2014b)

Superior temporal gyrus cortex

DARPP-32

Decrease: protein (Kunii et al. 2011a)

Caudate nucleus

DARPP-32

No alterations: mRNA (Kunii et al. 2014a)

t-DARPP-32

No alterations: mRNA (Kunii et al. 2014b)

Striatum

DARPP-32

Increase: protein phosphorylation (Kunii et al. 2011b)

t-DARPP-32

Increase: (Kunii et al. 2014b)

Anterior cingulate cortex

DARPP-32

No alterations: mRNA (Baracskay et al. 2006)

Thalamus

DARPP-32

No alterations: mRNA (Clinton et al. 2005)

Lymphocytes

DARPP-32

Decrease: protein (Torres et al. 2009)

No alterations: RNA (Cui et al. 2015)

Bipolar disorder

Dorsolateral prefrontal cortex

DARPP-32

Decrease: protein (Ishikawa et al. 2007)

No alterations: (Kunii et al. 2014a)

t-DARPP-32

Increase: mRNA (Kunii et al. 2014b)

Hippocampus

DARPP-32

Increase: mRNA (Kunii et al. 2014a)

t-DARPP-32

Increase: mRNA (Kunii et al. 2014b)

Caudate

DARPP-32

No alterations: (Kunii et al. 2014a)

t-DARPP-32

No alterations: (Kunii et al. 2014b)

Lymphocytes

DARPP-32

Decrease: protein (Torres et al. 2009)

Parkinson disease

Putamen

DARPP-32

Decrease: protein (Cash et al., 1987)

No alterations: protein (Girault et al., 1989)

Substantia nigra pars reticulate

DARPP-32

Decrease: protein (Cash et al. 1987)

Substantia nigra pars compacta

DARPP-32

Decrease: protein (Cash et al. 1987)

Caudate nucleus

DARPP-32

No alteration: protein (Girault et al. 1989)

Bipolar Disorder (BD): Three studies reported alterations in DARPP-32 levels in BD patients. The levels of DARPP-32 are decreased in the dorsolateral prefrontal cortex of BD patients, indicating that DARPP-32 might be involved in the neurotransmission imbalance in the BD brain (Ishikawa et al. 2007). However, there is no alteration in the expression of DARPP-32 mRNA in the same brain region of patients (Kunii et al. 2014a). In contrast, the levels of expression of t-DARPP-32 are increased in the dorsolateral prefrontal cortex of patients. It was also reported an increase of DARPP-32 and t-DARPP-32 mRNA levels in the hippocampus, but not in caudate, of BD patients (Kunii et al. 2014b). Interestingly, chronic treatment with lithium increases the levels of DARPP-32 in prefrontal cortex of rats (Guitart and Nestler 1992). Furthermore, DARPP-32 levels are decreased in the lymphocytes of BD patients, pointing to DARPP-32 as a putative biomarker for BD (Torres et al. 2009) (see Table 1).

Major Depression (MD): Much evidence supports the involvement of dopamine in MD, for example, pharmacological treatment and dopamine metabolite levels. A recent study observed an increase of mRNA expression of both DARPP-32 and t-DARPP-32 in the dorsolateral prefrontal cortex of MD (Kunii et al. 2014b). On the other hand, there is no alteration in the DARPP-32 and t-DARP-32 mRNA levels in the MD patients’ hippocampus. Acute treatment with fluoxetine increases the phosphorylation of DARPP-32 in many regions of the mouse brain (Svenningsson et al. 2000b), and chronic treatment with lithium and antidepressants increases DARPP-32 levels in the prefrontal cortex of rats (Guitart and Nestler 1992; Reis et al. 2007). Another study reported that chronic electroconvulsive stimulation, which is very useful for depression, increases the levels of DARPP-32 in rats hippocampus and striatum (Rosa et al. 2007).

Attention Deficit and Hyperactivity Disorder (ADHD): ADHD affects 3–7% of children in the world. Dopamine signaling is the main target of pharmacological treatment. It was recently reported that methylphenidate treatment regulates the expression and phosphorylation of DARPP-32. Interestingly, these regulations are dependent on drug posology and the age of the rats and mice, and it is region specific as well (Fukui et al. 2003; Souza et al. 2009).

Parkinson Disease (PD): It is well known that dopamine signaling abnormalities are involved in the PD. Two studies reported different results regarding the levels of DARPP-32 in the brains of PD patients. One reported decreased levels of DARPP-32 in the putamen, substantia nigra pars reticulate and substantia nigra pars compacta of PD patients. However, no alterations in DARPP-32 levels were found in the putamen and caudate nucleus of a different group of PD patients (Cash et al. 1987; Girault et al. 1989) (see Table 1).

DARPP-32 and Drugs of Abuse

Since its discovery three decades ago, DARPP-32 has been shown in a large body of work as a central signaling molecule activated by a diverse array of neurotransmitters such as dopamine, glutamate, serotonin, adenosine, and gamma-aminobutyric acid (GABA). In response to drugs of abuse and psychostimulants, these neurotransmitters regulate the phosphorylation state of DARPP-32, which converts it to an inhibitor of either a protein phosphatase (PP1) or a protein kinase (PKA) (Belkhiri et al. 2016; Andersson et al. 2005).

Diverse addictive stimuli share the ability to enhance dopamine signaling and modulate reward-related learning and memory; yet, the responsiveness of humans and animal models to drugs is highly dependent on a variety of genetic and environmental factors that are not entirely understood. DARPP-32 functions as a switch, reinforcing or inhibiting the action of the cAMP-dependent pathway, depending on its state of phosphorylation (Engmann et al. 2015).

Cannabis: The major psychoactive components of marihuana and hashish are cannabinoid. Cannabis and its primary psychoactive active constituent, D9-tetrahydrocannabinol (THC), can produce addiction and neuropsychiatric symptoms with repeated use (Volkow et al. 2014). Fernández-Ruiz et al. (2010) showed that the effects of cannabinoids on dopamine transmission and dopamine-related behaviors are indirect and affected by the modulation of GABA and glutamate inputs received by dopaminergic neurons. Recent evidence suggests, however, that certain eicosanoid-derived cannabinoids may directly activate TRPV1 receptors (Fernández-Ruiz et al. 2010). These receptors have been found in some dopaminergic pathways, what allow a direct regulation of DA function by cannabinoid signaling. In the brain, cannabinoids interact with neuronal cannabinoid CB1 receptors (CB1Rs), thereby producing a marked reduction of motor activity. These receptors are coupled to Gs protein that enhances cAMP levels and, consequently, leads to the phosphorylation of DARPP-32 at Thr34. Point mutation of Thr75 does not affect the behavioral response to CP55940, a selective CB1Rs agonist. On the other hand, catalepsy induced by CP55940 is reduced in both DARPP-32 knockout mice and Thr34-Ala DARPP-32 mutant mice. Activation of CB1Rs, either by an agonist or by inhibition of reuptake of endogenous cannabinoids, stimulates phosphorylation at Thr34 (Reis et al. 2007; Andersson et al. 2005).

The stable transcription factor D FBJ murine osteosarcoma viral oncogene homolog B (DFosB) accumulates in striatal neurons during repeated administration of abused drugs, including THC (Lazenka et al. 2014). Dopamine signaling is regulated by DARPP-32, which is highly expressed in striatal medium spiny neurons (MSNs) and dopaminergic terminal fields (Greengard 2001; Nairn et al. 2004). THC-mediated phosphorylation of T34 DARPP-32 is inhibited by administration of a D1R or A2AR antagonist (Borgkvist et al. 2008), suggesting that both MSN populations contribute to cannabinoid-dopamine interactions. Lazenka et al. (2014) recently reported that repeated THC-mediated DFosB induction in the striatum was abolished in mice lacking CB1Rs (Lazenka et al. 2014). Genetic deletion of DARPP-32 enhances THC-mediated hypolocomotion as well as the development of tolerance to this response after repeated THC administration, suggesting an involvement of DARPP-32-mediated signaling in the acute and chronic motor effects of THC (Lazenka et al. 2015).

Cocaine: Acute treatment with cocaine increases the phosphorylation of DARPP-32(Thr34) and decreases the phosphorylation ofDARPP-32(Thr75). On the other hand, chronic treatment with cocaine increases phosphorylation of DARPP-32(Thr75) and decreases phosphorylation of DARPP-32(Thr34) (Svenningsson et al. 2004).

Chen et al. (2008) demonstrated that acute stimulation with cocaine activates the dopamine D1 receptors, consequently leading to DARPP-32(Thr34) phosphorylation in the striatum. Several studies have shown that DARPP-32 participates in the progressive development of behavioral sensitization to cocaine. Knock-out of DARPP-32 or DARPP-32 mutation (threonine 34 replaced by alanine) in mice attenuated the hyperlocomotor activity induced by acute cocaine treatment. Moreover, chronic treatment with cocaine decreased phosphorylation at Thr34 but increased at Thr75. This latter effect was due to enhanced Cdk5 (Chen et al. 2008).

Ro 60–0175, 5-HT2CR agonist, inhibited cocaine-induced phosphorylation of DARPP-32 at threonine residues in the nucleus accumbens (NAc) core and the selective 5-HT2CR antagonist SB 242084 reversed this effect. These findings demonstrate that 5-HT2CRs are capable of modulating mesoaccumbens dopamine pathway activity at postsynaptic level by specifically controlling dopamine signaling in the NAc core subregion (Cathala et al. 2015).

Acute and repeated cocaine exposures had been shown to induce changes in the expression of many genes in the brain (Robison and Nestler 2011). Such transcriptional modifications can be rapid and transient, or persistent and account for long-term behavioral changes following repeated exposure. It has been shown that cocaine also acts on DNA methylation involving DNA methyltransferases (DNMTs) and methyl-CpG binding domain proteins (MBDs) (Host et al. 2011). While cocaine inhibits PP1 activity through at least dopamine D1 receptors and DARPP-32 phosphorylation, very little is known about the mechanism by which the expression of each PP1C isoform is regulated (Bodetto et al. 2013).

Opiates: Opiates act on the dopaminergic system in the brain via the μ-receptor and modulates the expression of DARPP-32, which represents an interesting nexus for drug-induced changes in neural long-term synaptic plasticity. Mahajan et al. (2009) showed that heroin significantly increased both D1 and DARPP-32 gene expression. Also, it has been demonstrated that that gene silencing DARPP-32 by siRNA in cultured normal human astrocytes cells modulated the activity of downstream effectors molecules, such as PP-1 (Mahajan et al. 2009). Opiates, such as morphine, bind to opioid receptor subtypes (mu, delta, and kappa) that are abundant in the striatum. Mu- and delta-receptors are coupled to Gi protein, which decreases phosphorylation of DARPP-32 at Thr34 and modulates both dopamine and adenosine receptor activation (Reis et al. 2007).

Ignatowski et al. (2015) investigated the role of DARPP-32-mediated signaling on withdrawal behavior in a rat model of opiate addiction, using intracerebral administration of gold nanorods (GNR) complexed to DARPP-32 siRNA to silence DARPP-32 gene expression and measure its effects on the opiate withdrawal syndrome. The results showed that opiate-addicted animals treated with GNR-DARPP-32 siRNA nanoplex showed a lack of condition place aversive behavior consequent to the downregulation of secondary effectors such as PP-1 and CREB, which modify transcriptional gene regulation and consequently neuronal plasticity. Thus, nanotechnology-based delivery systems could allow sustained knockdown of DARPP-32 gene expression, which could be developed into a therapeutic intervention for treating drug addiction by altering reward and motivational systems and interfere with conditioned responses (Ignatowski et al. 2015).

Nicotine: Nicotine is the critical component in tobacco smoke that is involved in addiction. It has been shown that nicotine modulates dopaminergic neurotransmission mainly by enhancing dopamine release in nigrostriatal and mesolimbic dopaminergic systems. Abdolahi et al. (2010) demonstrated incubation of drug seeking following widespread access to nicotine self-administration and suggested that enhanced PKA signaling in the insular cortex via phosphorylation of DARPP-32 at Thr34 is associated with this effect. At low concentrations, nicotine decreases phosphorylation of DARPP-32 at Thr34 in mouse neostriatal slices. In the other hand, high levels of nicotine increased the phosphorylation of DARPP-32 at Thr34 (Abdolahi et al. 2010). Therefore, different concentrations of nicotine lead to a different amount of dopamine release and, consequently distinct activation patterns of dopamine receptors (Reis et al. 2007).

Kuroiwa et al. (2012) investigated the function of muscarinic receptors in the striatum by monitoring DARPP-32 phosphorylation at Thr34 using mouse striatal slices and showed that muscarinic receptors, especially M5 receptors, act at presynaptic dopaminergic terminals, regulate the release of dopamine in cooperation with nicotinic receptors, and activate D1 receptor/DARPP-32 signaling in the striatonigral neurons. Muscarinic M1 receptors expressed in striatopallidal neurons interact with adenosine A2A receptors and activate DARPP-32 signaling (Kuroiwa et al. 2012).

Shin et al. (2012) studied therapeutic potential of agents affecting the dopamine system in traumatic brain injury model and showed that damage reduced pDARPP-32-T34 levels, but nicotine treatment of injured animals did not alter pDARPP-32-T34 levels, indicating that postsynaptic dopamine signaling is complex, and the restoration of dopamine release may not be sufficient for the recovery of DARPP-32 activity (Shin et al. 2012).

Ethanol: Ethanol does not have a clearly defined site of action. It can act directly as an agonist of GABAA and antagonist of NMDA receptors and indirectly as an agonist of dopamine D1 receptor. Studies with DARPP-32 knockout mice showed DARPP-32 involvement in ethanol reward induced behavior in both place preference and self-administration tests (Risinger et al. 2001). It has been demonstrated that moderate levels of ethanol increase phosphorylation of DARPP-32 at Thr34 in striatal slices. Ethanol administration was found to increase phosphorylation of DARPP-32 (Thr34) in the nucleus accumbens (NAc) and amygdala (but not in the striatum) of wild-type and transgenic mice, with a greater effect in the amygdala of transgenic mice. It was also found to increase of DARPP-32 (Thr75) in the amygdala of the wild-type mice only and the NAc and striatum of both the transgenic and wild-type mice. The authors concluded that the effect of ethanol on the balance of DARPP-32 phosphorylation, especially in the amygdala, may contribute to differential motivational effects of ethanol (Nairn et al. 2004; Goodman 2008).

The reinforcing properties of ethanol are in part attributed to interactions between opioid and dopaminergic signaling pathways. Björk et al. (2010) report that an acute ethanol challenge induces a robust phosphorylation of DARPP-32 (Björk et al. 2010). Abrahao et al. (2014) showed that the functional hyperresponsiveness of D1 receptors in the nucleus accumbens is associated with an increased phospho-Thr34-DARPP-32 expression after D1 receptor activation (Abrahao et al. 2014).

Summary (Future Directions, Perspective, Questions, or Challenges)

The importance of DARPP-32 arises from its relationship to several different signaling systems/cascades involved in intracellular functions such as important as gene expression, cell differentiation, metabolism, and neuronal plasticity. The protein is an integrator of cellular function and as such, a putative target to fine tune those functions. Also, research should be conducted to gather information from animal models such as the Caenorhabditis elegans, Drosophila melanogaster, Aplysia sp., and Zebrafish. An example, in Caenorhabditis elegans, “Area-Restricted Search” behavior is controlled by a dopaminergic response to food deprivation that modulated glutamatergic signaling. Dopaminergic pathway compounds are not entirely described, and, like humans, this behavior time course is on order of minutes, so a similar process might explain, and a DARPP-32 like protein could be part of it.

Future research will certainly shed more light on the roles of DARPP-32 in different biological processes, as well as potential new functions. Nanotechnology is having an increasing impact in the healthcare industry. The combination of diagnostic (imaging) and therapeutic capability enables the “real-time” monitoring of therapeutic progression, thus bringing “personalized medicine” closer to clinical reality. Bonoiu et al. (2009) introduced a nanotechnology approach that utilizes gold nanorod-DARPP-32 siRNA complexes that target to dopaminergic signaling pathway in the brain. Gene silencing of the nanoplexes in dopaminergic neuronal cells was evidenced by the reduction in the expression of key proteins, as DARPP-32, belonging to this pathway, with no observed cytotoxicity. Since these nanoplexes were shown to transmigrate across an in vitro model of the blood–brain barrier, it appears to be suited for brain-specific delivery of appropriate siRNA for therapy of drug addiction and other brain diseases. Nevertheless, the available collection of evidence suggests that DARPP-32 lies at the nexus of multiple signaling pathways that modulate critical signaling states of a given cell type, thus assuring that it will continue to be an important molecule in the quest to find new pharmacological targets.

References

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Daniela V. Rosa
    • 1
  • Luiz Alexandre V. Magno
    • 1
  • Bruno R. Souza
    • 1
    • 2
  • Marco A. Romano-Silva
    • 1
  1. 1.Faculdade de Medicina, Instituto Nacional de Ciência e Tecnologia – Medicina MolecularUniversidade Federal de Minas GeraisBelo HorizonteBrazil
  2. 2.Departamento de Fisiologia e BiofísicaUniversidade Federal de Minas GeraisBelo HorizonteBrazil