Dopamine heteroreceptor complexes as therapeutic targets in Parkinson's disease.

Review

Dopamine heteroreceptor complexes as therapeutic targets in Parkinson’s disease 1.

Introduction

2.

Heteroreceptor complexes between dopamine receptor subtypes

3.

D2R heteroreceptor complexes

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with receptors recognizing another transmitter/modulator 4.

D1R heteroreceptor complexes with receptors recognizing another transmitter/modulator

5.

Conclusion

6.

Expert opinion

Kjell Fuxe†, Diego Guidolin, Luigi F Agnati & Dasiel O Borroto-Escuela †

Karolinska Intitutet, Department of Neuroscience, Stockholm, Sweden

Introduction: Several types of D2R and D1R heteroreceptor complexes were discovered in the indirect and direct pathways of the striatum, respectively. The hypothesis is given that changes in the function of the dopamine heteroreceptor complexes may help us understand the molecular mechanisms underlying the motor complications of long-term therapy in Parkinson’s disease (PD) with l-DOPA and dopamine receptor agonists. Areas covered: In the indirect pathway, the potential role of the A2AR-D2R, A2AR-D2R-mGluR5 and D2R-NMDAR heteroreceptor complexes in PD are covered and in the direct pathway, the D1R-D3R, A1R-D1R, D1R-NMDAR and putative A1R-D1R-D3R heteroreceptor complexes. Expert opinion: One explanation for the more powerful ability of l-DOPA treatment versus treatment with the partial dopamine receptor agonist/ antagonist activity to induce dyskinesias, may be that dopamine formed from l-DOPA acts as a full agonist. The field of D1R and D2R heteroreceptor complexes in the CNS opens up a new understanding of the wearing off of the antiparkinson actions of l-DOPA and dopamine receptor agonists and the production of l-DOPA-induced dyskinesias. It can involve a reorganization of the D1R and D2R heteroreceptor complexes and a disbalance of the D1R and D2R homomers versus non-dopamine receptor homomers in the direct and indirect pathways. Keywords: allosteric receptor--receptor interactions, dimerization, dopamine D1 receptor, dopamine D2 receptor, dopamine heteroreceptor complexes, dopamine receptor agonists, dyskinesias, G-protein-coupled receptors, homodimerization, l-DOPA, motor complications, neurodegeneration, Parkinson’s disease Expert Opin. Ther. Targets [Early Online]

1.

Introduction

Parkinson’s disease (PD) is a common neurodegenerative disease, the major motor features of which are bradykinesias, tremor and rigidity. The discovery of dopamine in the brain and the locomotor actions of l-DOPA in rodent models of PD [1,2] together with discovery of the nigrostriatal dopamine pathway in rat brain [3,4] inspired the introduction of l-DOPA therapy in the treatment of PD [5-7]. Indications for their existence in the monkey brain were also obtained [8]. The degeneration of the nigro-striatal dopamine pathway was postulated to be the major cause of the motor features of PD. For the first time, an effective symptomatic treatment of rigidity, akinesia and tremor was developed and the progression of the disease was not enhanced [9]. Since the mapping of the nigro-striatal dopamine neurons, we were interested in finding dopamine receptor agonists for treatment of PD. Our idea was that dopamine may not be formed from l-DOPA in sufficient amounts in remaining dopamine nerve terminals to reach in relevant concentrations via diffusion in the extracellular space all the synaptic and extrasynaptic dopamine receptors which 10.1517/14728222.2014.981529 © 2014 Informa UK, Ltd. ISSN 1472-8222, e-ISSN 1744-7631 All rights reserved: reproduction in whole or in part not permitted

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Article highlights. .

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Potential role of D1R-D3R. A1R-D1R, D1R-NMDAR and the putative A1R-D1R-D3R heteroreceptor complexes in the direct pathways. Potential role of A2AR-D2R, A2AR-D2R-mGluR5 and the D2R-NMDAR heteroreceptor complexes in the indirect pathway. D1R and D2R heteroreceptor complexes open up a new understanding of wearing off effects of antiparkinsonian drugs and l-DOPA-induced dyskinesias.


This box summarizes key points contained in the article.

lack close by dopamine nerve terminals [10]. This view was related to our belief of the existence of extrasynaptic dopamine communication which we later on called volume transmission (VT) [11]. Thus, dopamine receptor agonists had the potential advantage that they should reach all the striatal dopamine receptors. We discovered both non-ergot and ergot dopamine receptor agonists [10]. The first dopamine receptor agonist to be found was apomorphine. Ernst obtained indications in a pharmacological analysis of behavioral effects of apomorphine, namely gnawing compulsion, for its dopamine agonist action [12]. This was validated the same year by the AndenFuxe groups [13] through studies on turning behavior and demonstrations of apomorphine-induced reductions of dopamine turnover. Apomorphine today is a well-known antiparkinson drug, which activates all dopamine receptor subtypes like l-DOPA [14]. In 1968, Ungerstedt introduced his pioneering 6-OHDA rat model of unilateral PD, which allowed a precise quantitation of the behavioral action of dopamine agonists [15,16]. Dopamine receptor agonists and L-DOPA produced contralateral rotational behavior due to supersensitivity development in the striatal dopamine receptors on the lesioned side. In 1971, we tested ET-495 (generic name Piribedil, a piperonyl-piperazine derivative) in the Ungerstedt model in view of its cardiovascular effects because it induced hypotension and l-DOPA was known to produce orthostatic hypotension. It produced contralateral turning behavior like l-DOPA and apomorphine and reduced striatal dopamine turnover [17]. It had only weak effects on dopamine release [18]. Through a collaboration in 1973 with Menek Goldstein’s group, it was possible to show that it produced antitremor actions and involuntary movements in a monkey model of PD via actions at dopamine receptors [19]. Based on these results, clinical trials were performed and showed its antiparkinson actions [20,21]. It was characterized as a D2/D3 agonist with a2A and a2C blocking activities [22]. The most exciting development was our demonstration that an ergopeptide 2-Br-a ergocryptine better known under the generic name bromocriptine was a dopamine receptor agonist [23,24]. The reason for testing it was that we knew that the tuberoinfundibular dopamine neurons, which Fuxe had discovered in 1963 [25,26], were likely involved in the regulation of prolactin 2

secretion [27]. Furthermore, Fluckiger had shown that it could inhibit prolactin secretion [28,29]. Bromocriptine belonged to the cyclic peptide group of ergoline derivatives (ergopeptides). It mimicked the actions of apomorphine and l-DOPA in the Ungerstedt hemiparkinsonian rat model but produced a substantially more prolonged contralateral rotational behavior due to its long-lasting dopamine receptor stimulation. Long-lasting antitremor actions were also demonstrated in a monkey model of PD with ventromedial tegmental lesions [30]. Under the leadership of Drs. Lieberman and Menek Goldstein, we could demonstrate in 1976 the antiparkinsonian efficacy of bromocriptine in PD [31]. It validated the results of Calne et al. from 1974 [32]. Our demonstration in 1978 with Dr Robert Schwarcz that bromocriptine mainly acted at dopamine receptors not linked to adenylate cyclase (AC) was of substantial interest and was one of the first indications of the existence of subtypes of dopamine receptors [33]. This receptor became known as the D2R. Bromocriptine became one of the most used antiparkisonian drugs after L-DOPA for many years. Thus, the work on bromocriptine and piribedil emphasized the importance of activating the D2-like receptors in treatment of PD. Many ergot drugs were found to be dopamine receptor agonists or better dopamine partial agonists, the ratio of agonist-antagonist activity varying with the dopamine receptor population studied [34,35]. Bromocriptine showed, for example, weak partial agonist activity at the D1R [34,35]. The most potent agonists appeared to be the ergot drugs of the clavine type, such as agroclavine and elymoclavine, were found to clearly act on both the D1R and D2R subtypes [34]. They seemed to represent potential antiparkinson drugs of high interest but were not developed further. Today a number of ergot-derived therapeutics are implicated in the development of cardiac valvulopathy due to 5-HT2B receptor agonism [36,37] and have therefore been withdrawn from treatment of PD. The most used dopamine agonists today in PD are non-ergot D2R/D3R agonists such as ropinirole (indolinone derivative) and pramipexole (tetrahydrobenzothiazole) [38]. It should be noted that these types of dopamine agonists appear to be more likely than l-DOPA in producing pathological gambling in PD patients [39]. It may potentially be related to activation of limbic D2R/D3R receptors [40,41] leading to elicitation of AC supersensitivity development [42]. The dopamine receptors are part of the class A family of G-protein-coupled receptors (GPCRs), which represent the rhodopsinlike receptors [43]. Two groups of dopamine receptors exist, the D1-like (D1R, D5R) and the D2-like (D2R, D3R, D4R) receptors. Of highest importance for understanding the therapeutic actions and side effects of l-DOPA and dopamine receptor agonists in the treatment of PD is the discovery that many D2R and D1R heteroreceptor complexes exist in the brain [44-52]. In these receptor complexes, allosteric receptor--receptor interactions are in operation altering GPCR recognition, pharmacology, trafficking, signaling and thus the function of the participating GPCR protomers. It gives diThrsity and bias to the dopamine receptor protomers [47]. Moonlighting proteins are defined as a

Expert Opin. Ther. Targets (2014) ()

Dopamine heteroreceptor complexes as therapeutic targets in Parkinson’s disease


Table 1. Heteroreceptor complexes containing dopamine D1R subtype. Heteroreceptor complex

Location

Signaling

Potential relevance for PD

D1R-D2R

Subsets of MSNs in accumbens (DYN, ENK, GABA/glutamate) [58]

Gq/11, Ca2+ release via IP3, recruitment of BDNF via CaMK-II and MeCP2 are blocked by D1R and D2R antagonist. SKF83959 D1R-D2R heteromer agonist

D1R-D3R

Certain striato-nigral GABA neurons [72]

D3R enhancement of D1R affinity and postsynaptic signaling

D1R-A1R

Striato-endopeduncular-nigral GABA pathway and prefrontal cortex [44,138,139]

A1R agonist uncouples the D1R to its Gs/ olf protein leading to desensitization. A1R agonist inhibits D1R-induced hyperactivity, EEG arousal, oral dyskinesias. Neuronal A1R increase kynurenic acid

Hyperdopaminergia increases function of D1R-D2R heteromer, mental side effects with L-DOPA and D2R agonist including addiction [60,179] D3R enhances D1R-induced locomotion and dyskinesias [68,69] A1R antagonists enhance motor activity. A1R agonists may reduce L-DOPA-induced dyskinesias [44,102,140]

Hippocampus, striatum (synapse) [145,149]

D1R reduced NMDA currents and excitotoxicity, NMDA increased D1R signaling. D1R activation upregulates NMDA-dependent LTP and promotes working memory and NR1-CaMK-II coupling

D1R-D3R-A1R D1R-NMDAR (NR1)

Postulated [110,132] Cognitive dysfunction after uncoupling of the receptor complex [180]

BDNF: Brain-derived neurotrophic factor; LTP: Long-term potentiation; PD: Parkinson’s disease.

multifunctional protein where different functions are found in single strands of amino acids not linked to splicing and posttranslational modifications and so on. [53]. Dopamine receptor protomers can moonlight through the allosteric receptor--receptor interactions in GPCR heteromers leading to, for example, changes in recognition, G-protein selectivity and switching to b-arrestin-mediated signaling [46,47,54]. Dopamine D1R and D2R protomer functions may also change by becoming linked to receptor tyrosine kinases (RTK) and to ion channel receptors. For the overall architecture of the global GPCR heterodimer network, see Borroto-Escuela et al. [52]. The GPCRs of class A can exist as monomers, dimers and higher order homo- and heteroreceptor complexes forming a puzzle of different molecular sizes. Fluorescence correlation spectrometry analysis in cellular models shows that D1R can freely diffuse in the plasma membrane mainly as homodimers [55]. However, there seems to be a specific momomer/ dimer equilibrium for class A GPCRs as shown for the corticotropin-releasing factor receptor type 1 in the endoplasmic reticulum [56]. This ratio appears to be constant also in the plasma membrane in spite of agonist activation of the receptors. There probably exists a dynamic equilibrium between the homodimers and the heteroreceptor complexes in the plasma membrane, which is still not characterized including their agonist regulation. In this review, we discuss the different D1R (Table 1) and D2R (Table 2) heteroreceptor complexes in the brain and their relevance for the dopaminergic treatment of PD. Changes in the function of the dopamine heteroreceptor complexes may especially help us understand the molecular mechanisms underlying the complications of long-term therapy with l-

DOPA and dopamine receptor agonists. This involves, in particular, the wearing off of their therapeutic actions including the appearance of the on-off phenomenon and the development of dyskinesias.

Heteroreceptor complexes between dopamine receptor subtypes

2.

D1R-D2R heteroreceptor complexes This receptor complex was discovered by the group of George and O’Dowd [57] and found upon coactivation of the D1R and D2R protomers to generate a phospholipase C-mediated calcium signal through Gq/11 activation in the striatum [48,58]. This signaling links the D1R-D2R heteromer to calcium/ calmodulin-dependent protein kinase II aa (CaMK-II), brain-derived neurotrophic factor formation and neuronal growth [59]. It is located especially in subsets of dynorphin/ encephalin medium spiny neurons of the nucleus accumbens. Also, a D1R-D2R heteromer agonist SKF 83959 was discovered showing its unique pharmacology [48] due to the allosteric receptor--receptor interactions leading to conformational changes in the orthosteric binding sites of the D1R and D2R protomers (Figure 1) (Tables 1 and 2). This heteroreceptor complex is implicated in drug addiction, schizophrenia and depression [60-62]. Of special interest is the demonstration that a small D1R sequence from the C-terminal tail containing 404Glu and 405Glu [63] can disrupt the D1-D2 receptor heteromer and block its signaling [62] likely through interference with a strong electrostatic interaction between the C-terminal tail of the D1R protomer and the intracellular loops of the D2R protomer [64,65]. 2.1


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Table 2. Heteroreceptor complexes containing dopamine D2R subtype. Heteroreceptor complex

Location

Signaling

Potential relevance for PD

D2R-D1R

Subsets of MSNs in accumbens (DYN, ENK, GABA/glutamate) [58]

Hyperdopaminergia increases function of D1R-D2R heteromer, mental sideeffects with L-DOPA and D2R agonist including addiction [60,179]

D2R-D3R

Ventral striatum [83]

Gq/11, Ca2+ release via IP3, recruitment of BDNF via CaMK-II and MeCP2, blocked by D1R and D2R antagonist, inactivation of GSK-3b. SKF83959 D1R-D2R heteromer agonist Partial D2R agonists turn into D2R antagonists at the D2R-D3R heteromer

D2R-D4R

Striatum [87,88]

D2R-NMDAR (NR2B)

Striatal glutamate synapses [133]

D2R-A2AR

Striato-pallidal GABA neurons, striatal cholinergic interneurons

Partial D2R agonists in PD treatment have reduced mental side-effects


[41,84]

[44,46,47,103]

D2R-A2AR-mGluR5

Striato-pallidal GABA neurons.

Combined D2R and D4R agonist treatment resulted in potentiating effects on ERK1/2 phosphorylation for D4.2R, D4.4R but not for D4.7R containing heteromers [87] This complex blocks CaMK-II-NR2B interaction with reduction of NR2B phosphorylation and NMDAR currents. Disruption of the D2R-NR2B complex reduced cocaine-induced locomotion The complex is increased by cocaine. Antagonistic A2AR-D2R receptor--receptor interactions in the heteroreceptor complex and at the AC level. D2R recognition, Gi/o coupling and signaling reduced [45,181]. A2A agonist blocked D2R-induced LTD and restored LTP [109] A2AR-mGluR5 synergize to reduce D2R recognition and Gi/o coupling and signaling [45,120,124]. Interactions also at the level of the signaling cascades: MAPK and CREB-P. A2AR and mGluR5 agonists synergistically increase GABA release in ventral pallidum [125]

The synergistic effects on ERK signaling may increase plasticity responses to L-DOPA treatment. The D4.7 variant may be linked to ADHD [87,88] Reduction of dopamine VT in PD can reduce the formation of the D2RNMDAR complex increasing the NMDA-mediated synaptic glutamate drive [133] A2AR antagonists may significantly target the A2A protomer. They increase locomotion, contralateral turning behavior after subthreshold doses of L-DOPA and D2 like agonists. No worsening of dyskinesia. Antidepressant activity [107,110] MGluR5 antagonists and negative allosteric modulators may significantly target the mGluR5 protomer. They increase locomotion and exert antiparkisonian actions and antidyskinetic actions specially combined with A2A antagonists [126,127,129,130]

AC: Adenylate cyclase; BDNF: Brain-derived neurotrophic factor; LTD: Long term depression; LTP: Long term potentiation; PD: Parkinson’s disease; VT: Volume transmission.

Intraventricular injections of the TAT-D1 peptide reduced behavioral despair and produced antidepressant effects [62]. Based on this exciting work, it seems possible that mental side effects of l-DOPA and dopamine agonist treatment such as hallucinations, psychosis, punding and gambling [66,67] can involve activation of the D1R and D2R protomers of this heteroreceptor complex in the nucleus accumbens. D1R-D3R heteroreceptor complexes D1R-D3R heteromers were discovered by FRET and BRET techniques in cotransfected mammalian cells [68,69]. Indications for the existence of striatal D1R-D3R heteroreceptor complexes were obtained by the demonstration of their coimmunoprecipitation in the striatum [69,70]. Previously, D3R had been shown to be expressed to a low degree in some of the D1R-positive substance P-dynorphin neurons of the direct pathway [71] and to a high degree in D1R-positive neurons of the nucleus accumbens shell and the Calleja islands [72]. It is 2.2

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substantial interest that in the hemiparkinsonian rat model, increased levels of D3R develop in the D1R-positive direct pathway upon l-DOPA treatment [73] indicating an increased formation of D1R-D3R heteroreceptor complexes in the direct pathway. It was found to be linked to l-DOPA-induced sensitization, a model of l-DOPA-induced dyskinesias. The analysis of the allosteric receptor--receptor interactions in these receptor complexes revealed that agonist induced activation of the D3R protomer increased the D1R agonist affinity at the orthosteric site of the D1R protomer both in cellular models and in striatal membrane preparations [68]. Furthermore, D3R protomer activation enhanced the D1R protomer signaling over the AC increasing the cAMP formation in spite of the fact that D3R via Gi/o is known when singly expressed to inhibit AC-PKA signaling [69,70]. The explanation is likely that the D3R protomer in this complex is weakly coupled to Gi/o and instead operates via the allosteric receptor--receptor interaction to enhance D1R signaling



D1R-D2R

D1R-D3R

SKF-83959


Gq/11 2+ binding PLC-β, IP3. Ca

Postsynaptic signalling

D1R-D3R-A1R

D1R-A1R

D1R homo-receptor complex Gs/olf binding Gs/olf binding & signalling D1R-NMDA (NR1)

Gs/olf signalling Upregulation of NMDA dependent LTP

Figure 1. Receptor--receptor interactions in different types of dopamine D1R heteroreceptor complexes in the CNS. The homo- and heteroreceptor complexes would allow direct physical interactions between the receptors making possible the allosteric receptor--receptor interactions between them. The balance between these receptor complexes determines the final functional output and thus the final cellular response. The schematic representation depicts some of the principal, nonexclusive, molecular mechanisms by which D1R heteroreceptor complexes produce novel types of signaling in the direct pathway.

over Gs/olf, which involves increased D1R agonist recognition (Figure 1). The trafficking of the D1R also changes when forming a heteroreceptor complex with the D3R [69]. The D1R agonist-induced internalization of the D1R protomer is strongly counteracted in the D1R-D3R heteroreceptor complex. However, upon coactivation of the D1R and D3R protomers cointernalization and cotrafficking develops similar to the one seen with the D1R homoreceptor complex. D1R-D3R heteromers have therefore been implicated in motor disturbances, especially l-DOPA-induced

dyskinesias [74], because D1R and D3R activation participate in their development as demonstrated in pharmacological analyses [75-78]. Pathologically enhanced signaling in the D1R protomer of the D1R-D3R heteroreceptor signaling of the direct pathway (striato-pallidal internal/nigral GABA neurons) known to produce motor activation can therefore contribute to the lDOPA-induced dyskinesias [74]. The molecular mechanism can involve sustained activation of DARPP-32 and ERK1/2 signaling through failure of D1R protomer internalization [78-80]. This can lead to changes in the phosphorylation of


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D1R-D2R

D2R-D3R Partial D2R agonist turn into full antagonist

SKF-83959


Gq/11 2+ binding PLC-β, IP3. Ca

D2R-NMDA (NR2B)

D2R-D4R

Block of CaMK-II recruitment Reduction of NMDAR phosphorylation

D2R homo-receptor complex

D2R-A2AR-mGluR5

Gi/o binding & signalling

MAPK

D2R-A2AR

AC/cAMP

MAPK AC/PKA

β-arrestin

Figure 2. Receptor--receptor interactions in different types of dopamine D2R heteroreceptor complexes in the CNS. The homo- and heteroreceptor complexes would allow direct physical interactions between the receptors making possible the allosteric receptor--receptor interactions between them. The balance between these receptor complexes determines the final functional output and thus the final cellular response. The schematic representation depicts some of the principal, non-exclusive, molecular mechanisms by which D2R heteroreceptor complexes produce novel types of signaling in the indirect pathway. AC: Adenylate cyclase.

ion channels and of receptors and in the transcription factorinduced formation of adapter proteins in the direct pathway. This can contribute to the formation of pathological longlived heteroreceptor complexes which can produce abnormal 6

motor programs with errors in the firing patterns and failure of depotentiation when triggered inter alia by the exaggerated D1R protomer signaling [81,82]. Thus, the development of brakes of overactivated D1R protomer signaling in different



types of homo- and heteroreceptor complexes of the direct pathway can be a valid strategy for counteracting l-DOPAinduced dyskinesias. D2R-D3R heteroreceptor complexes In cellular models, indications were obtained that D2R-D3R heteroreceptor complexes are formed based on coimmunoprecipitation analysis [83]. Also, cotransfected D2R and D3R fragments produced functional receptors binding D2R/D3R agonists and antagonists (Figure 2) [41,84]. Based on the distribution of colocated D2R and D3R, these heteroreceptor complexes may exist as autoreceptor complexes in the dopamine neurons and in a postjunctional position of the meso-limbic dopamine neurons. It is of substantial interest that the antiparkisonian drugs pramipexol and ropinirole, which are preferential agonists at D3R versus D2R, show an increased potency to activate D2R-D3R heteroreceptor complexes versus D2R homomeric complexes [41,84,85]. The mechanism may involve allosteric receptor--receptor interactions in the D2R-D3R heteroreceptor complex by which the agonistinduced activation of the D3R protomer can enhance Gi/o coupling of the D2R protomer to the AC. It, therefore, seems possible that the increased incidence of pathological gambling with these preferential D3R agonists [42] can involve the potent targeting of the limbic D2R-D3R heteroreceptor complexes. The pharmacological properties of the D2R-D3R heteroreceptor complexes were also characterized with regard to partial D2R/D3R agonists including aripiprazole [86]. It is suggested that the antipsychotic action of these partial D2R/ D3R agonists is related to their ability to block the D2R protomer in the limbic D2R-D3R heteroreceptor complexes [86]. The failure to exert partial D2R agonist activity at the D2R protomer in this receptor complex may be inhibitory allosteric communication from the D3R protomer, which alters the pharmacological properties of the orthosteric binding pocket of the D2R protomer through conformational changes. As a consequence, the partial D2R-D3R agonist can only bind as a D2R antagonist. Such a mechanism can also explain the low incidence of extrapyramidal side effects with these compounds, because the D2R-D3R heteroreceptor complexes in the dorsal striatum are likely to exist in very low densities.


2.3

D2R-D4R heteroreceptor complexes D2LR-D4.2R, D2LR-D4.4R and D2LR-D4.7R heteroreeptor complexes were discovered in cellular models using coimmunoprecipitation, in situ Proximity Ligation Assays and BRET1 techniques [87]. As seen from the reduced BRETmax values and the increased BRET50 values, the D4.7R was the least effective in forming such receptor complexes. Studies on their allosteric receptor--receptor interactions were also performed by analysis of the D2R agonist and D4R agonist interactions on ERK1/2 phosphorylation. In line with the BRET analysis, the D4R agonist PD168077 enhanced the D2R agonist-induced ERK phosphorylation in the 2.4

D2LR-D4.2R and D2LR-D4.4R heteromers but not in the D2LR-D4.7R heteromers (Figure 2) [87]. These results suggested the existence of facilitatory receptor--receptor interactions in the D2LR-D4.2R and D2LR-D4.4R heteroreceptor complexes leading inter alia to increased affinity of the D2R protomer agonist binding sites. Similar results on BRET were obtained using instead the short isoform of D2R (D2SR) [88]. It is of interest that in striatum of mice expressing a short intracellular loop3 of the D4R enhancing D2R-D4R receptor--receptor interactions on ERK1/2 phosphorylation were also seen but not in knock-in mice with a seven repeat intracellular loop3 (D4.7R) [88]. The D2R and D4R partially overlap in their distribution of the dorsal striatum and can be located both in dendritic shafts and spines [89]. They may potentially be colocated on striatal glutamate terminals because D2R activation enhances the D4R agonist-induced inhibition of glutamate outflow [88]. It should be noted that D4.7R seems to favor homomerization versus heteromerization with D2Rs [87,90]. Thus, D4R appear to form oligomers with different affinities and dimerization importantly participates also in their biogenesis. Taken together, D2R-D4.2R and D2R-D4.4R heteroreceptor complexes may exist in the striatum and be targets for antiparkinsonian drugs, especially l-DOPA and apomorphine since they can also activate D4Rs. A detailed understanding of their function and potential dysfunction in PD is lacking. However, the synergistic effects on ERK signaling may increase plasticity responses especially to L-DOPA treatment in PD patients.

D2R heteroreceptor complexes with receptors recognizing another transmitter/ modulator

3.

A2AR-D2R heteroreceptor complexes The first indications of adenosine and DA interactions in the basal ganglia were obtained by the demonstration that the methylxanthines caffeine and theophyllamine could enhance the actions of l-DOPA and dopamine receptor agonists in the Ungerstedt hemiparkinson model in rats [91]. In 1976 with Fredholm in studies on phosphodiesterase inhibitors, we proposed that adenosine mechanisms could be involved [92]. Based on the introduction of the receptor--receptor interaction concept [93], the existence of adenosine receptor-DA receptor interactions in the basal ganglia was postulated. In the 1990s, antagonistic A2AR--D2R interactions at the level of D2R recognition were found in striatal membrane preparations from naive and hemiparkinson rats [94-97]. These results led to the proposal that A2AR antagonists can be novel antiparkinson drugs by targeting the A2AR protomer in a putative A2AR-D2R heteroreceptor complex setting free D2R protomer signaling (Table 2) [44]. The A2ARs and D2Rs are colocated especially not only in the striato-pallidal GABA neurons at the soma-dendritic level 3.1


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but also in the striatal cholinergic interneurons [98-100] and on the cortico-striatal glutamate terminals [101,102]. The A2ARD2R heteroreceptor complexes were first demonstrated in cellular models with inter-alia coimmunoprecipitation and BRET/FRET techniques and found to form constitutive receptor complexes [103-105]. The A2AR-D2R heteroreceptor complexes in the striatum were later on demonstrated with proximity ligation assays seen as red clusters in many neurons in ventral and dorsal striatum with regional differences in density [51,106]. The antagonistic A2AR-D2R receptor--receptor interaction in the receptor complexes takes place not only at the level of D2R recognition but also at the level of Gi/o activation and D2R protomer signaling (Figure 2) [44,45,107,108]. However, the A2AR agonist activated receptor--receptor interaction is proposed not only to inhibit Gi/o signaling and act as a filter. Instead, it will change the function of the D2R protomer through a conformational change (moonlighting) with reduced binding of Gi/o and increased binding of b-arrestin leading to a dominance of b-arrestin signaling (Figure 2) [46,54]. Furthermore, it is well-known that A2AR activated Gs/olf and D2R activated Gi/o antagonistically interact at the AC level [101,102]. Also, in neuroplasticity antagonistic A2ARD2R receptor--receptor may occur. Thus, an A2AR agonist blocked D2R-induced long-term depression and restored long-term potentiation [109]. The antagonistic A2AR--D2R interaction was also demonstrated at the level of the striatopallidal GABA pathway and its brain circuits in naive rats and in a rat model of PD [110-112]. In view of above the A2AR protomer in the A2AR-D2R heteroreceptor complex in the dorsal striato-pallidal GABA neurons with antagonistic A2AR-D2R receptor--receptor interactions is likely to be a significant target for A2AR antagonists with regard to antiparkinsonian effects. The enhancement of locomotion and contralateral turning behavior in PD models by A2AR antagonists after subthreshold doses of L-DOPA and D2R-like agonists can elegantly be explained by a reduction in the antagonistic A2AR-D2R [113].

striato-pallidal GABA neurons leading to an enhanced excitatory state and thus to increased motor inhibition. Increased A2AR homomer-monomer signaling increases protein phosphorylation plasma membrane receptors and ion channels via DARPP-32 thr34-induced protein phosphatase-1 inhibition. Furthermore, the PKA-induced transcriptional activation can involve formation of special adaptor proteins, which may stabilize pathological heteroreceptor complexes leading to abnormal firing patterns in the striato-pallidal GABA neurons and to formation of abnormal motor programs. This contributes to the appearance of l-DOPA and dopamine agonist-induced dyskinesias due inter alia to a partial failure of l-DOPA and dopamine agonists to induce via D2R an appropriate dynamic inhibition of the striatopallidal GABA neurons setting free motor activity. Thus, only certain movements which are not planned can be produced while others are inhibited in spite of D2R activation by l-DOPA and dopamine receptor agonists. More A2ARD2R heteromers can also be formed with remaining D2Rs on the plasma membrane. Thus, an increased A2AR brake on the D2R protomer signaling in the heteromer may also develop upon chronic l-DOPA and dopamine receptor agonist treatment. These mechanisms may also strongly contribute to the wearing off of the therapeutic effects of L-DOPA and dopamine receptor agonists, since motor inhibition cannot be efficiently removed. This can also be due to increased dominance of A2AR signaling in homomers and A2AR-D2R heteromers with increased firing and thus failure of the L-dopa to exert a downstate of the striato-pallidal GABA neurons. As a consequence, the motor brake is not sufficiently removed. Taken together, both A2AR homomers and A2AR protomers in A2AR-D2R heteromers in the striato-pallidal GABA neurons may be significant targets for A2AR antagonists with regard to antiparkinsonian and possible antidyskinetic actions and in diminishing the wearing off of the therapeutic effects of L-DOPA.

3.1.1

On the role of the balance in A2A and D2 receptor signaling

3.1.2

The antidyskinetic indications found with A2AR antagonists in PD patients in 2003 [114,115] were unexpected to us in view of their blockade of the antagonistic A2AR--D2R interaction. In order to understand these actions of A2AR antagonists, we proposed in 2006 that the balance between A2AR homomers versus A2AR-D2R and D2R homomers plays an important role in controlling the activity and gene expression in the striato-pallidal GABA neurons [81]. Thus, an upregulation especially of A2AR homodimers will take place due to l-DOPA-induced increases through multiple mechanisms of phospho-CREB formation activating CRE in the A2AR promotor. Furthermore, a downregulation of the D2Rs develops upon chronic l-DOPA treatment. Thus, a dominance of A2AR over D2R signaling exists in the

MitoPark mice represent a genetic model with a progressive degeneration of the nigral dopamine nerve cells [116]. The most interesting result was that chronic A2AR antagonist MSX-3 treatment prevented the progressive reduction of spontaneous locomotor activity observed in saline or L-DOPA-treated animals studied 23 h after last injection as the nigrostriatal dopamine neurons degenerated [117]. Our results indicate that chronic treatment with A2AR antagonists should be tested as monotherapy in early PD, and serves to remind us that positive behavioral effects of such treatment need not be reflected in terms of rescue of striatal DA levels. We hypothesize that early and chronic A2AR antagonist treatment maintains spontaneous activity through blockade

8

Effects of the A2AR antagonist MSX-3 in the Mito-Park model in mice




of the reorganization of the A2AR oligoreceptor complexes and associated changes in the function of A2AR and other participating protomers in the striato-pallidal GABA neurons induced by the progressive dopamine cell degeneration. A number of reviews have recently been published on results obtained in the clinical trials with the A2AR antagonists [118,119]. It is clear that in contrast to the results obtained in animal models of PD, the A2AR antagonists are rather modest as to their antiparkinson actions. They are effective in reducing off-time, without worsening troublesome dyskinesia, and in increasing on-time with a mild increase of non-troublesome dyskinesia, in patients at an advanced stage of PD treated with L-DOPA. One possible explanation is that the treatment with A2AR antagonist must start early and be chronic to stop reorganization of the A2AR heteroreceptor complexes and their signaling pathways in response to the degeneration of the dopamine nerve terminal networks (see above). However, additional explanations may be an enhanced placebo effect.

A2AR-D2R-mGluR5 heteroreceptor complexes We should also consider another important mechanism, namely the existence of A2AR-D2R-mGlu5 higher order heteroreceptor complexes [120] with multiple receptor--receptor interactions antagonizing D2R protomer signaling [110,111,121,122] in finding explanations for the weak to modest clinical actions of A2AR antagonists (Figure 2). These complexes appear to be colocated extrasynaptically on dendritic spines of the striato-pallidal GABA neurons [123]. In PD, there may develop a strong brake on D2R protomer signaling in such receptor complexes through a dominance of coactivated A2AR and GluR5R receptor protomer signaling. This may take place especially after chronic L-DOPA and D2R agonist treatment which may enhance a reorganization of the A2AR-D2R-mGluR5 heteroreceptor complexes in relation to the corresponding homomeric receptor complexes [81]. A2AR and mGluR5 receptors synergize to reduce D2R recognition, Gi/o coupling and synergistic interactions take place between them in the signaling cascades of the MAPK and pCREB pathways (Figure 2) [45,124]. At the level of the striato-pallidal GABA neurons, A2AR and mGluR5 agonists perfused in the nucleus accumbens synergistically increased GABA release in ventral pallidum using dual probe microdialysis [125]. mGluR5 antagonists increase locomotion and exert antiparkinsonian actions and antidyskinetic actions especially combined with A2AR antagonists [102,124,126-130]. So in the treatment of PD, we may need a combined blockade of A2AR and mGluR5 receptors potentially achieved through use of heterobivalent compounds with A2A antagonist and mGlu5 antagonist/negative allosteric modulator pharmacophors to remove the brake on D2R protomer signaling. Small molecular compounds with combined A2AR and mGluR5 antagonist activity or heterotrimer specific A2AR or mGluR5 antagonists are other attractive options (Figure 3). 3.2

Thus, a major target for treatment of PD is this extrasynaptic heterotrimer receptor complex located in the local circuit of the striato-pallidal GABA neurons and activated by glutamate, adenosine and DA VT signals in the extracellular space. It demonstrates how synaptic glutamate through extrasynaptic VT and synaptically and glially derived ATP by transformation into adenosine can further bring down D2R-mediated VT in PD [123,131,132]. The A2AR-D2R-mGluR5 heterotrimer receptor complex may also exist prejunctionally on the glutamate terminal of this local circuit where the combined activation of the mGluR5 and A2AR protomer can strongly counteract the inhibitory actions of D2R protomer activation on glutamate release. Taken together, in PD, there is an increased glutamate drive in the indirect pathway due to loss of the inhibitory extrasynaptic dopamine VT mediated via D2R leading to increased extrasynaptic glutamate VT and adenosine VT and activity in the striato-pallidal GABA pathway with increased motor inhibition. This will also further bring down signaling of the D2R protomer in the A2AR-D2R-mGluR5 heterotrimer receptor complex. It should strongly contribute to the wearing off of the L-DOPA action in PD by putting a brake on D2R signaling. It may require early treatment of drugs with A2AR and mGluR5 antagonistic properties before irreversible reorganization of the A2AR-D2R-mGluR5 heteroreceptor complexes and other receptor complexes have taken place. This combined treatment should also counteract the lDOPA and dopamine agonist-induced dyskinesias since the brake on D2R signaling in this receptor complex should be removed allowing the D2R protomer to exert its inhibitory actions on the striato-pallidal GABA neurons and motor inhibition can be substantially reduced. The motor initiation by the direct pathway, which is enhanced by l-DOPA through activation of D1R, can therefore take place with reduced motor inhibition from the indirect pathway. This should help reduce the development of dyskinetic movements due to distortion of the movements caused by differential inhibition of certain movements through the partial brake on D2R signaling and increased excitatory and synergistic signaling over A2AR and mGluR5 receptors in the indirect pathway. This leads to varying increases in activity of its subsystems and differential inhibition of movements induced by the D1R-rich direct pathway. The cortical motor command of this motor inhibition system via the glutamate synapses can no longer function properly in view of the disbalance in inhibitory D2R-mediated and excitatory A2AR and mGluR5-mediated fine tuning of the striato-pallidal GABA neurons that develops in the progression of PD involving also a brake on D2R protomer signaling. The adaptive changes taking place with chronic l-DOPA and dopamine agonist treatment will worsen this disbalance and increase the brake on D2R signaling which contribute to the development of l-DOPA and dopamine agonist-induced dyskinesias and the wearing off of the antiparkinson actions.


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Dopmaine D2R monomer

Dopmaine D2R heteromers

Dopamine Heterobivalent drugs

Amiloride


[D2R]

Gα γ

β

[D2R]

[A2AR]

[D2R]

[A2AR] [mGluR5 /mGluR5]

Figure 3. Intra- and intermolecular allosteric receptor--receptor interactions of dopamine D2R subtype. Allosteric mechanisms make possible the integrative activity taking place intramolecularly in the D2R monomers (left) or intermolecularly in D2R homo/heteromers (right). One example of the intramolecular allosteric mechanisms is the allosteric binding of amiloride to the extracellular site of D2R, which modulates the recognition of the orthosteric dopamine D2R binding site via a conformational change. Intermolecular allosteric mechanisms take place through the formation of different types of D2R homo/heteromers and receptor/protein complexes which can change the function of an individual receptor protomers present in a receptor homomer or heteromer. One approach for drug development based on the intermolecular heteromer interactions is the use of heterobivalent ligands containing a D2R agonist and an A2AR antagonist pharmacophor linked through a spacer of variable size. They may function as useful molecular probes for targeting the A2AR-D2R heteromer and in this way counteracting the A2AR-D2R antagonism of the D2R protomer. The right panel shows an A2AR-D2R-mGlu5 higher order heteroreceptor complex with multiple receptor--receptor interactions antagonizing D2R protomer signaling. A2AR and mGluR5 receptors synergize to reduce D2R recognition, Gi/o coupling and signaling and synergistic interactions take place between them in the signaling cascades of the MAPK and pCREB pathways. A combined blockade of A2AR and mGluR5 receptors potentially achieved through use of heterobivalent compounds with A2A antagonist and mGlu5 antagonist/negative allosteric modulator pharmacophors could remove the brake on D2R protomer signaling in PD. PD: Parkinson’s disease.

D2R-NMDAR (NR2B containing) heteroreceptor complexes

3.3

Liu et al. [133] demonstrated that NR2B subunit of the NMDAR can directly interact with the D2R. It was located postsynaptically in the striatal glutamate synapses. The D2R activation reduced the signaling of the NMDA receptors (Figure 2). This heteroreceptor complex is likely located in the glutamate synapses located on the striato-pallidal GABA neurons. Thus, dopamine via diffusion into the glutamate synapse can then reduce NMDAR signaling in this receptor complex via activation of the D2R protomer. This should reduce the glutamate-induced activation of the indirect pathway and bring down motor inhibition. Antiparkinsonian actions of NR2B-selective receptor antagonists were reported in animal models of PD which included a marked enhancement of the motor activation produced by l-DOPA [134,135]. It seems possible that the NR2B-selective antagonists may have a special value when the pathological glutamate drive on the striato-pallidal GABA pathway is a major factor in producing motor inhibition in PD. This mechanism should also 10

lead to increased extrasynaptic glutamate VT from the cortico-striatal glutamate synapse on this pathway which will increase the activation of the mGluR5 protomer of the A2AR-D2R-mGluR5 heteroreceptor complex. This will increase the brake on the D2R protomer signaling through the allosteric receptor--receptor interaction (see above). Combined treatment with NR2B-selective NMDA antagonist and an mGluR5 antagonist/negative allosteric mGluR5 modulator should therefore be considered as an interesting future strategy for treatment of PD. The drawback is that the NR2B-selective NMDA antagonist may also block such excitatory receptors involved in activating the direct pathway mediating motor activation and in learning and memory. In patients with moderate PD single dose therapy with such an antagonist did not lead to a relevant increase in motor function [136]. There is no clinical evidence that NR2B-selective antagonists can reduce l-DOPA-induced dyskinesias [76]. However, it is of substantial interest that disrupting the interaction of the NR2B subunit with members of the membrane-associated guanylate kinase protein family in



hemiparkinsonian rats induces dyskinesias in nondyskinetic rats treated with l-DOPA [137].

D1R heteroreceptor complexes with receptors recognizing another transmitter/ modulator

4.

A1R-D1R heteroreceptor complexes Heteroreceptor complexes of A1Rs and D1Rs were demonstrated with coimmunoprecipitation in cotransfected Ltk-fibroblast cells [138] and later on in striatum using also this technique [139]. With BRET and FRET, further evidence was later on obtained for their existence in A1R and D1R cotransfected cell lines [140]. Antagonistic allosteric A1R-D1R receptor--receptor interactions were found in these complexes as seen from the substantial reduction of D1Rs in the high-affinity state induced by A1R agonists in cellular models and in striatal membrane preparations [44,140]. The high-affinity state of the A1R is necessary for this antagonistic interaction to develop and requires the binding of adenosine deaminase to the A1R [141]. It is well-known that the Gi/o coupled A1R antagonistically also interact with the Gs/olf coupled D1R at the AC level (Figure 1) (Table 1). The A1R--D1R interactions likely exist in the D1R positive striato-entopeduncular/nigral GABA pathway (direct pathway) [44]. Antagonistic A1R-D1R interactions exist in the regulation of GABA release and of immediate early genes in this pathway of the hemiparkinsonian rat [44]. Antagonistic interactions also take place in D1R agonist-induced motor effects in rodents [142,143]. Of special interest is the demonstration that A1R agonists in rabbits can counteract D1R agonist-induced oral dyskinesias [144]. In view of the role of D1Rs in mediating l-DOPAinduced dyskinesias [80], these observations offer the potential that early coadministration with A1R agonists especially through antagonistic receptor--receptor interactions in A1RD1R heteroreceptor complexes can counteract development of l-DOPA-induced dyskinesias. In support of this view, it was found that D1R agonists can produce a disruption of the A1R-D1R heteroreceptor complexes removing the antagonistic A1R-D1R interactions in cell lines [138]. This action was blocked by cotreatment with the A1R agonist. Such changes may also take place in the striatum [139]. One important mechanism for the potential antidyskinetic actions of A1R activation is likely the counteraction of induction of long-term increases in D1R protomer signaling upon chronic l-DOPA treatment. As discussed earlier, it is possible that upon chronic l-DOPA treatment, D1R induced increases in transcription factor activation (formation of adapter proteins) via the AC-PKA-CREB pathway and the activation of the DARPP-32 Thr34 leading to protein phosphatase-1 inhibition, will reorganize multiple heteroreceptor and homoreceptor complexes in the postsynaptic membrane. This will lead to novel integration of the signaling especially in their


4.1

glutamate synapses and thus to marked changes in synaptic plasticity and in the formation of short-term and long-term memories [82]. This may cause the appearance of pathological firing patterns in the direct pathway initiating movements, which may be out of cortical control and lead to dyskinesias when l-DOPA is given. This postsynaptic reorganization may also help reorganize the presynaptic receptor complexes through, for example, retrograde signaling assisted by changes in the firing pattern of the cortico-striatal glutamate pathways to match the novel memory traces represented by the novel pattern of postsynaptic and also extrasynaptic receptor complexes on the postjunctional side. As discussed (see Section 2.2), the formation of D1R-D3R heteroreceptor complexes in the direct pathway may increase in models of PD based on increased expression of D3Rs [75]. This mechanism likely contributes to development of lDOPA-induced dyskinesias through allosteric receptor-receptor interactions increasing D1R signaling. It has therefore been postulated that A1R-D1R-D3R heteroreceptor complexes may exist in the direct pathway in PD (Figure 1) [111]. A1R protomer activation induced via agonists may cause a brake on D1R-D3R signaling in this heterotrimeric receptor complex to a level necessary to obtain the therapeutic actions of l-DOPA but avoiding the development of the dyskinesias. The A1R-induced inhibition of glutamate release may also contribute. The A1R pharmacology should be tested in cellular models with A1R-D1R and A1R-D1R-D3R heteroreceptor complexes as targets. D1R-NMDAR heteroreceptor complexes The existence of D1R-NMDAR heteroreceptor complexes with allosteric receptor--receptor interactions was discovered by Fang Liu et al. (Figure 1) [145]. One region of the C-terminal tail of the D1R protomer interacted with the NR1-1A subunit. This direct interaction was disrupted by agonist activation of the D1R protomer that allowed the C-terminal tail of NR1 to recruit calmodulin and PI3K, which led to its activation. As a consequence, NMDAR excitotoxicity was reduced. Another region of the D1R Cterminal tail interacted with the NR2A subunit, which may reduce the plasma membrane expression of the NMDAR protomer on the plasma membrane and thus also NMDAR protomer signaling. It is unclear under which conditions one type of allosteric receptor--receptor interaction may dominate over the other one. Overall, these D1R-NMDAR receptor--receptor interactions appear to provide protection against the consequences of overactivation of NMDAR protomer signaling ion these receptor complexes. It should be noted, however, that via the cytoplasmic cascades leading to increases in protein phosphorylation the D1R increases NMDAR signaling [146-148]. In 2003, it was demonstrated that the D1R coimmunoprecipitated with NMDAR subunits in postsynaptic densities from striatum likely in the D1R-positive direct pathway [149]. In cellular models, indications were obtained for the 4.2


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constitutive formation of D1R-NMDAR heteroreceptor complexes in the endoplasmic reticulum which then were targeted to the plasma membrane [149]. It is of interest that within this heteroreceptor complex, the D1R protomer failed to internalize and thus to desensitize. In 2004, in line with the above results, NMDAR activation was found to increase the density of D1Rs on the plasma membrane and to increase D1R signaling through insertion of D1Rs into the cell surface via the D1R-NR1 interaction [150]. These observations in 2003 and 2004 are relevant for understanding the development of l-DOPA-induced dyskinesias in PD because a compensatory increased glutamate drive may have developed in the direct pathway due to loss of the dopamine D1R-mediated transmission on the direct pathway. The subsequent increase in NMDAR signaling can then recruit an increased number of D1R-NMDAR heteroreceptor complexes to the postsynaptic membrane. This may assist in producing exaggerated increases in D1R signaling to l-DOPA which upon chronic l-DOPA treatment can reorganize the D1R heteroreceptor complexes, and also other receptor complexes via changes in protein phosphorylation and in transcriptional factor activation with formation of novel adapter proteins. As discussed in Section 2.2, the formation of D1R-D3R heteroreceptor complexes can also contribute to this reorganization of the postsynaptic membrane. This involves the formation of novel long-term memories leading to pathological motor programs in the motor circuits as the errors in the pattern of firing in the direct and indirect pathways become integrated. Finally in 2006, observations were made in organotypic cultures from striatum that NMDAR activation reduced the D1R diffusion coefficient in dendritic spines [151]. Their lateral diffusion appears to be reduced by an activated NMDAR forming a trap for diffusing D1Rs in the plasma membrane by formation of a putative D1R-NMDAR heteroreceptor complex. The impact on D1R and NMDAR protomer function remains to be explored. In support of a role of NMDARs in l-DOPA-induced motor complications, clinical trials with the NMDAR antagonist amantadine may indicate that amantadine can reduce lDOPA-induced dyskinesias [152]. However, the duration of the benefit of amantadine appears to be reduced over a period of months [153]. More clinical work on NMDAR antagonists is required especially because amantadine has several other actions including noradrenaline and DA releasing activity [154]. Thus, other mechanisms may be involved. 5.

Conclusion

Taken together the current research on D1R and D2R heteroreceptor complexes in the basal ganglia offers a novel molecular mechanism for understanding the wearing off of the antiparkinson actions of l-DOPA and dopamine receptor agonists and the development of l-DOPA and dopamine receptor agonist-induced dyskinesias. In this way, new 12

strategies for the treatment of motor function deficits in PD can be offered with reduced motor complications. However, the motor deficits due to degeneration of non-dopaminergic neurons will remain [155]. 6.

Expert opinion

Ever since the non-ergot and ergot dopamine receptor agonists like apomorphine, piribedil and bromocriptine were discovered in the late 1960s and in 1970s and shown to have antiparkinson effects in rodent and monkey models of PD, the question has been if they have any advantages versus l-DOPA treatment in PD. Today, it seems as if the major advantage of dopamine receptor agonists is that they can postpone in early PD the use of l-DOPA, which gives a higher incidence of dyskinesias in PD patients versus ropinirole and pramipexol [156-158]. l-DOPA remains the major treatment of late PD with major motor deficits. In recent years, continuous dopamine receptor stimulation via use of, for example, continuous release preparations was shown to markedly reduce dyskinesia development both with l-DOPA and dopamine receptor agonists like the short-acting dopamine receptor agonist apomorphine. Enteral l-DOPA/carbidopa gel infusion was found to significantly reduce plasma l-DOPA pulsativity and to produce marked increases in motor function with little induction of dyskinesias [159]. Thus, it seems as if the intermittent stimulation of the dopamine receptor subtypes in the D1R-positive direct and D2R positive indirect pathway has a major impact in reorganizing the D1R and D2R heteroreceptor complexes in the postsynaptic membranes of the efferent GABA pathways of the striatum. This may be related to the need of dynamic periods of activation of the D1R and D2R signaling cascades with sufficient alterations in protein phosphorylation and in transcription factors to produce adapter proteins leading to long-term reorganization of the heteroreceptor complexes in the postsynaptic membrane of the striato-pallidal interna/ nigral and striato-pallidal GABA pathways, respectively. In addition, the dopamine agonist-induced activation of the D1R and D2R protomers of the D1R and D2R heteroreceptor complexes can also via the allosteric receptor--receptor interactions lead to short term reorganization of the heteroreceptor complexes. These can become long-lived due to the formation of novel adapter proteins and increases in protein phosphorylation with increased negative charges in one protomer leading to strong electrostatic bonds formed with positively charged amino acid sequences in adjacent protomers in the heteroreceptor complexes. It is difficult to link the reduced incidence of dyskinesias found with high-affinity dopamine receptor agonists like the non-ergot agonists ropinirole, pramipexole and rotigotine versus l-DOPA to their ability of activating only a certain subtype of dopamine receptor. Thus, only ropinirole is selective for D2-like receptors (D2R, D3R and D4R) while pramipexole and rotigotine show high affinity also for D1-like




receptors [160]. Also, it was demonstrated that selective D2-like agonists, including piribedil [19,161], can cause dyskinesias in monkey models of PD. A D1R agonist ABT-431 likewise can induce dyskinesias similar to l-DOPA in parkinsonian patients [162]. In fact, in rodent models of PD D1R agonists produced dyskinesias to a similar extent as l-DOPA [163] and D1R but not D2R antagonists can block them [80]. These results emphasize, at least in rodent models of PD, a more important role of D1Rs versus D2Rs in induction of dyskinesias. It should be considered that the dyskinesias induced by D2R-like agonists such as ropinirole and piribedil is produced not only via a strong chronic inhibition of the striato-pallidal GABA neurons and reduction of motor inhibition but also by their D3R agonist activity in the direct pathway. Here, they can target the D3R protomer in the D1R-D3R heteroreceptor complexes of this pathway (see Section 2.2) and produce via an allosteric receptor--receptor interaction a chronic enhancement of D1R protomer signaling with enhancement of activity in the direct pathway leading to motor activation. Thus, the D3R agonist activity of dopamine receptor agonists can contribute both to their antiparkinsonian activity and to induction of dyskinesias. One explanation for the more powerful ability of l-DOPA treatment to induce dyskinesias may be that the dopamine formed from l-DOPA acts as a full agonist at all the dopamine receptor subtypes of the striatal heteroreceptor complexes in contrast to the partial agonist/antagonist activity of the different types of dopamine receptor agonists in use in treatment of PD [10,34,35]. This hypothesis may explain also why apomorphine can produce not only strong antiparkinsonian actions but also induce dyskinesias similar to l-DOPA [164]. Thus, apomorphine appears to be an almost full agonist at D1Rlike and D2R-like receptors. It seems as if the full long-term reorganization of the D1R and D2R heteroreceptor complexes in the direct and indirect pathways, respectively, which leads to marked dyskinesias according to our hypothesis, requires the pulsatile activation of the D1R and D2R protomers in their heteroreceptor complexes and the full agonist activity of dopamine formed from l-DOPA. It is of interest that continuous administration of rotigotine can reduce the dyskinesias induced by pulsatile treatment with l-DOPA in common marmosets [165]. Thus, the reorganized heteroreceptor complexes seem to require the pulsatile and full agonist activity of l-DOPA to induce the changes in the neurophysiological activity of the direct and indirect pathways leading to dyskinesias. It is of substantial interest that the altered firing patterns in the direct and indirect pathways in a rodent model of PD can be restored by a D2Rlike agonist [166]. In contrast, the D1R agonist fails to normalize the pattern of firing in the direct pathway. These results again open up the possibility that the D3R agonist activity of the D2R-like agonists at the D1R-D3R heteroreceptor complexes is of importance for restoring normal activity also of the direct pathway and thus for their therapeutic actions.

It is true so far that the dopamine receptor agonists used in the clinical studies failed to indicate a reduction of the progression of PD. In view of the discovery of FGFR1-A2AR and FGFR1-5-HT1AR heteroreceptor complexes [51,167-170], it should be considered dopamine receptors also can participate in RTK-GPCR heteroreceptor complexes. Thus, in such complexes agonist activation of dopamine receptor protomers may produce transactivation of RTK signaling leading to potential neuroprotective and neurotrophic actions. In fact, it was shown that D2R agonists increased the formation of D2R-EGFR heteroreceptor complexes in neuroblastoma cells based on increased coimmunoprecipitation of these two protomers [171]. This will be an interesting new field for exploring novel strategies for counteraction of the PD progression [46,110,132]. Striatal FGFR1-A2AR-D2R heteroreceptor complexes were also postulated. The field of D1R and D2R heteroreceptor complexes in the CNS opens up a new understanding of the role of nondopaminergic receptors in PD and how they lead to novel strategies for treatment of PD [46,101,102,129]. Here, we have mainly discussed the adenosine A1R- dopamine D1R heteroreceptor complexes in the direct pathway and A2AR-D2R and A2AR-D2R-mGluR5 heteroreceptor complexes in the indirect pathway and their impact on the progression of PD and its treatment. The A2AR antagonists were introduced in the treatment of PD based on the antagonistic A2AR-D2R receptor--receptor interaction which will increase as dopamine terminals progressively disappear in PD with a dominance of A2AR signaling in homomers and A2AR-D2R heteroreceptor complexes versus D2R signaling [81]. This will lead to an enhanced activity in the indirect pathway and thus to motor inhibition. Through the receptor--receptor interaction an A2AR protomer-mediated brake on D2R protomer signaling will inter alia develop. It is therefore surprising that A2AR antagonists so far only show a modest improvement of the motor functions in PD. One reason may be that they should be given early to PD patients to stop the reorganization of the A2AR-D2R and other A2AR heteroreceptor complexes in the striatum as the PD progresses. Blocking the A2AR protomers may then have reduced antiparkinson consequences. Another reason may be that the major role in controlling D2R signaling is played by the A2AR-D2R-mGluR5 heteroreceptor complex in the dendrites of the striato-pallidal GABA neurons [120]. Here, the brake on D2R protomer signaling may be brought about by combined increases in activity in both A2AR and mGluR5 protomers which act synergistically to put a strong brake on D2R protomer signaling via allosteric receptor--receptor interactions [45,132]. Thus, combined treatment with A2AR and mGluR5 antagonists with or without l-DOPA may be an important strategy for treatment of PD in restoring motor function and counteracting the wearing off of the l-DOPA action by removing the brake on D2R signaling in the indirect pathway. D2R inhibition of this pathway returns and motor inhibition can be removed. Ideally, we should target the heterotrimeric receptor


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complex by developing heterobivalent compounds with mGluR5 and A2AR antagonist pharmacophors or pharmacophors with negative allosteric mGluR5 and A2AR modulating properties. A2AR-D2R-mGluR5 heterotrimer specific A2AR and mGluR5 antagonists would be another interesting option to remove the brake and counteract the wearing off of the chronic l-DOPA action and markedly increase the on time. It should reduce side effects of these antagonists. A1R antagonists increase the antiparkinson actions of D1R agonists in animal models of PD [44,102]. These effects may in part be produced by blocking the antagonistic A1R-D1R interaction in the A1R-D1R heteroreceptor complexes in the D1R positive direct pathway. The activity of this pathway is enhanced by D1Rs and leads to motor activation. However, A1R antagonists have not been tested in PD patients so their antiparkinson properties remain to be demonstrated in the clinic. The role of the synaptic D2R-NMDAR (NR2B) and D1RNMDAR (NR1and NR2A) heteroreceptor complexes in the indirect and direct pathways in PD also remain to be demonstrated. So far, NMDAR antagonists have not shown any antiparkinson actions in PD probably due to the fact that they block the excitatory NMDARs in both the direct pathway which increases motor activation and in the indirect pathway which causes motor inhibition. The net effect may therefore be no change in motor performance. The hypothesis introduced on the molecular mechanism for development of l-DOPA-induced dyskinesias involving a reorganization of the D1R and D2R heteroreceptor complexes in the direct and indirect efferent pathways and a disbalance of the signaling of dopamine receptor homomers versus non-DA receptor homomers in these pathways [81] is of substantial interest. It gives a novel understanding of the mechanism for the antidyskinetic actions of several drugs. mGluR5 antagonists like 2-methyl-1homomer signli,3thiazol-4-ylethynylpyridine (MTEP) are known to demonstrate highly significant antidyskinetic actions [130,172]. The mechanism can involve a reduction of the dominance of excitatory mGluR5 signaling in mGluR5 homomers and in A2AR-D2R-mGluR5 heteroreceptor complexes versus D2R signaling in D2R homomers and in these heteroreceptor complexes in the striato-pallidal GA neurons. This will restore at least in part the D2R-mediated inhibition of the activity of the indirect pathway. This will reduce motor inhibition and produce antiparkinsonian actions which may help the direct pathway to initiate normal motor activity as it integrates with the indirect pathway. It should also be considered that the blockade of the Gq/11-mediated mGluR5 signaling reduces PKC-MAPK signaling and CREB phosphorylation which may reduce increases in gene expression with reduced formation of adapter proteins and inhibit receptor and protein phosphorylation in the plasma membrane. This may reduce the l-DOPA and disease-induced reorganization of these heteroreceptor complexes into novel complexes with 14

an increased brake on D2R signaling through increased inhibitory allosteric receptor--receptor interactions mediated via mGluR5 and A2AR protomers. mGluR5 receptors also exist in the direct pathway, and their inhibition may reduce an exaggerated activity of this pathway via the strong l-DOPAinduced activation of D1R protomer signaling in D1R-D3R heteroreceptor complexes (see above). Such an action can also contribute to the antidyskinetic activity of mGluR5 antagonists. The mechanism for the ability of A2AR antagonists to improve motor function in PD without worsening dyskinesias [114,129,173,174] is proposed to be due to their targeting of A2AR homomers and A2AR-D2R-mGluR5 heteroreceptor complexes in the striato-pallidal GABA pathway showing increased A2AR signaling in PD versus D2R signaling in homomers and these heteroreceptor complexes [81]. Thus, the balance in A2AR and D2R signaling in these receptor complexes can be restored and the A2AR antagonists as described for the mGluR5 antagonists above may also help counteract the reorganization of the A2AR-D2R-mGluR5 heteroreceptor complexes into a state with an increased brake on D2R protomer signaling. Our hypothesis is as discussed above that combined blockade of mGluR5 and A2AR receptors in early PD in homomers and in A2AR-D2R-mGluR5 heterotrimeric complexes would restore the balance of A2AR/mGluR5 and D2R signaling and remove the brake on D2R protomer signaling in this heteroreceptor complex. Therefore, combined treatment with these antagonists early in PD and later on with l-DOPA or dopamine receptor agonists as PD progresses is an exciting strategy for restoring motor function in early and late PD and for preventing motor complication to develop like dyskinesias, since motor inhibition is more effectively removed. It is clear that exaggerated D1R signaling in the direct pathway also is a major factor in producing l-DOPA-induced dyskinesias in rodent models of PD and likely also in PD [80,175]. This enhancement of D1R signaling is likely further increased by the formation of D1R-D3R heteroreceptor complexes in the direct pathway in PD through facilitatory D1R-D3R receptor--receptor interactions, which can contribute to the development of l-DOPA-induced dyskinesias [74]. The discovery of antagonistic A1R-D1R interactions in heteroreceptor complexes in the direct pathway is therefore of substantial interest [102,140]. The existence of A1R-D1RD3R heteroreceptor complexes in this pathway was in fact postulated [110,111,132]. Also, adenosine A1R agonists can reduce dyskinesias in rabbits [144]. It will therefore of importance to further document the antidyskinetic properties of A1R agonists in animal models of PD. Our view is that they may represent novel antidyskinetic compounds acting by increasing inhibitory A1R signaling in A1R homomers and in postulated A1R-D1R-D3R heteroreceptor complexes where the agonist activation of the A1R protomer can put a brake on D1R protomer signaling in the direct pathway. Also, the balance of inhibitory A1R homomer and excitatory




D1R homomer signaling becomes restored with a reduction of the pathologically increased activity in the direct pathway induced by the dominance of D1R signaling. Again the dominance of D1R signaling may lead to a longterm reorganization of the postulated A1R-D1R-D3R heteroreceptor complex through increases in protein and receptor phosphorylation and increased expression of adapter proteins. The associated changes in allosteric receptor--receptor interaction in this receptor complex may not allow the inhibitory A1R brake on D1R recognition and signaling to fully operate. The result is a pathological increase in the neuronal activity of the direct pathway leading to a pathological motor drive upon l-DOPA treatment strongly contributing to l-DOPA-induced dyskinesias. A number of studies indicate that the NMDAR antagonist amantadine can have antidyskinetic activity in PD patients but of limited duration [153]. It seems possible that the D1RNMDAR heteroreceptor complex can be one possible target for such an action since NMDAR activation may recruit D1R-NMDAR heteroreceptor complexes to the plasma membrane [150]. As a result, the D1R signaling is increased in the direct pathway which should increase the development of l-DOPA-induced dyskinesias. Our hypothesis also gives a new possibility to understand the mechanism for the ability of high frequency electrical stimulation (deep brain stimulation) of the subthalamic nucleus to counteract both motor deficits and l-DOPABibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

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Declaration of interest This work has been supported by the Swedish Medical Research Council (62X-00715-50-3) and AFA F€orsa¨kring (130328) to DO Borroto-Escuela and K Fuxe. DO Borroto-Escuela belong to Academia de Bio´logos Cubanos. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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Affiliation

Kjell Fuxe†1 MD PhD, Diego Guidolin2 PhD, Luigi F Agnati3 MD PhD & Dasiel O Borroto-Escuela4 PhD MBA † Author for correspondence 1 Professor, Karolinska Institutet, Department of Neuroscience, Retzius va¨g 8, 17177 Stockholm, Sweden Tel: +46 852 487 077; Fax: +46 8 315 721; E-mail: [email protected] 2 University of Padova, Department of Molecular Medicine, Padova, Italy 3 Professor, University of Modena, Department of Biomedical Sciences, Modena, Italy 4 Karolinska Institutet, Department of Neuroscience, Retzius va¨g 8, 17177 Stockholm, Sweden Tel: +46 852 487 077; Fax: +46 8 315 721; Email: [email protected]

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