Dopamine receptors: Introduction
The existence of two types of dopamine receptors was first proposed in 1978 and 1979 on the basis of pharmacological and functional studies [45,70]. In particular the receptor that stimulates adenylyl cyclase and has low affinity for the antipsychotic drug sulpiride was referred to as the D1 while D2 was the receptor that inhibits cAMP formation and has high affinity for sulpiride [45,70]. That there were only two types of dopamine receptors was the dogma for over a decade. Then, beginning with the publication of the dopamine D2 receptor sequence in 1988 [12] subsequent gene cloning studies revealed the existence of 5 different genes that code for 5 distinct dopamine receptor subtypes- now referred to as D1, D2, D3, D4 and D5, and numerous isoforms generated by alternative splicing. Sequence analysis, pharmacological studies and evaluation of their ability to either stimulate or inhibit cAMP formation by coupling to Gαs/olf or Gαi/o proteins, however, reveal that all cloned dopamine receptor subtypes heterologously expressed in tissue culture cells can be grouped into one of the two initially recognized receptor categories. Dopamine receptors were thus divided into the D1-like and D2-like families (reviewed in [20,53,66,68] and [16]). D1-like receptors genes are intronless in their amino acid coding region and include D1 and D5 subtypes in mammals, as well as a third subtype in lower organisms [54]. The D2-like receptors include the D2, D3 and D4 subtypes. In mammals, the protein coding regions of the D2-like receptors contain introns and different isoforms have been identified as a result of alternative splicing (reviewed in [20,66,68] [53] and [16]). In particular two D2 receptor isoforms (D2-short and D2-long) have been identified, that differ in the presence or absence of a 29-amino acid domain in the third intracellular loop (reviewed in [20,66,68] and [53]) and display specific functional and signaling properties [18,38,48,61]. Splice variants of the D3 receptor and polymorphic variants of the D4 receptor have also been identified (reviewed in [68] and [53].
The identification of the five dopamine receptor subtypes, each with unique localization and properties, stimulated the effort to develop subtype-selective drugs to treat specific symptoms for disorders associated with dopaminergic dysfunctions, including Parkinson’s disease and schizophrenia. In particular, D2-like preferring agonists such as pramipexole, ropinirole, piribedil, rotigotine, and the ergot alkaloids pergolide, bromocriptine and cabergoline have proven useful for the therapy of Parkinson’s disease. Pergolide, ropinirole, pramipexole and rotigotine have a significant degree of selectivity for D2-like over D1-like dopamine receptors, and ropinirole, pramipexole, and rotigotine have higher affinity for the D3 vs. the D2 receptor [52,58]. Overstimulation of D1 receptor-mediated signaling in the striatum has been associated with the development of L-DOPA-induced dyskinesias in animal models of Parkinson’s disease [31,64,71,78]; the low affinity of D2/D3 agonists for the D1 receptor may be related to the low incidence of motor side effects of these drugs.
The mesocorticolimbic dopamine system is implicated in schizophrenia. A strong correlation exists, in fact, between the therapeutic effects of antipsychotics and blockade of the D2 dopamine receptor. Notably, all clinically approved antipsychotics are D2 receptor blockers. The second and third generation of antipsychotics, that target other receptors such as the serotonin 5-HT2A, and have a lower incidence of side effects, still possess antagonistic activity at D2 receptors [34] (and reviewed in [4]).
Evidence accumulating through the study of dopamine receptor signaling in the last ten years has pointed to a further degree of complexity within these receptor families. The canonical paradigm of dopamine receptor activation and signalling involves the sequential activation of G proteins and specific enzyme or channel effectors. However, this model is too simplistic to explain the functional flexibility of these receptors. It is now widely accepted that dopamine receptor signaling is not limited to activation or inhibition of adenylyl cyclase, but that dopamine receptors regulate multiple signaling pathways by interacting with various G proteins, by activating G protein-independent mechanisms and by interacting with ion channels and tyrosine kinase receptors (for review, see [4]).
The classical view of dopamine receptor signaling implies that the D1 receptor stimulates the cAMP/PKA/DARPP-32 pathway [5,37,72] while the D2 and, to a lesser extent, the D3 receptors inhibit this pathway (reviewed in [53]). More recent data suggest that activation of DARPP-32 results in inhibition of PP1 and activation of the mTOR complex 1 (mTORC1) leading to rpS6 phosphorylation [11,63-64,76]. Moreover, D1 receptor-mediated PKA activation also results in the activation of the extracellular signal-regulated kinases 1/2 (Erk1/2) by two mechanisms: src-Shp2-dependent Erk1/2 phosphorylation [30-31] and DARPP-32-mediated inhibition of protein phosphatase-1 [63]. It is believed that upregulation of these mechanisms, leading to aberrant Erk1/2 activation, are involved in the development of L-DOPA-induced dyskinesias in animal models of Parkinson’s disease [26,31,64,71]. Both D1-like and D2-like receptors also signal through alternative cAMP-independent pathways. In particular, there is evidence that D1 and D2 receptors modulate calcium channel activity by direct protein-protein interactions [46] (and reviewed in [4]) and that the D1 and D2 receptors modulate the Na+-K+ ATPase [10,41]. Moreover, both D1-like and D2-like receptors transactivate tyrosine kinase receptors [35,73,79]
The paradigm that dopamine receptors signal through G proteins has been recently unsettled by the observation that the D2 receptor may transduce signaling through G protein-independent, arrestin 2/3 (β-arrestin)-mediated mechanisms [4-5,7,9]. Beside their role in GPCR desensitization and internalization, arrestin 2 (β-arrestin1) and arrestin 3 (β-arrestin2), in fact, can act as molecular scaffolds for signaling effectors (reviewed in [4-5,7,9,49]). In particular, D2 receptor agonists promote the clustering of the D2 receptor, arrestin 2 (β-arrestin2), Akt and PP-2A into a molecular complex that allows PP-2A to dephosphorylate and inactivate Akt resulting in GSK3 activation ([4-5,7,9,23,69]. Modulation of the formation of this complex may represent a new mechanism to explain the effects of D2-related drugs. For example, it has been reported that lithium acts by inducing the dissociation of the D2/Akt/arrestin/PP-2A complex [6,8,55,57,75] and that all antipsychotics prevent agonist-induced arrestin 2/3 (β-arrestin) recruitment to the D2 receptor [51].
Another level of complexity involving dopamine receptors has been pointed out by evidence that, like many other GPCRs, dopamine receptors directly interact with members of the same family and with structurally divergent families of receptors to form heteromers with pharmacological, signaling and trafficking properties different from those of their constituent receptors (reviewed in [2,27,33]
The recent discovery of D2 receptor signaling heterogeneity has led to a reconsideration of the mechanism(s) of action of some antipsychotics [75] and to the development of “biased drugs” to selectively target arrestin 3 (β-arrestin2)-mediated D2 signaling in schizophrenia. This pathway is thought to significantly contribute to the effects of antipsychotics. In particular, all antipsychotics efficiently prevent agonist-induced arrestin 2/3 (β-arrestin) recruitment to the D2 receptor [51], while variably influencing D2-mediated inhibition of cAMP formation. For example, aripiprazole is a partial agonist for D2-related cAMP signaling and a full antagonist for the recruitment of arrestin 3 (β-arrestin2) to the D2R. This observation led to the development of compounds UNC9975, UNC0006 and UNC9994 that could represent the first attempt to develop partially biased agonists for the D2/arrestin/Akt/PP-2A pathway [1] (reviewed in [4]). These compounds bind to the D2 receptor and act as partial agonists for arrestin 3 (β-arrestin2) recruitment to D2 receptor, but are antagonists of cAMP signaling.
The discovery of the existence of dopamine receptor heteromers with atypical properties also opens the way to the development of new drugs. Receptor heteromers could represent, in fact, potential and promising targets for bifunctional compounds selectively acting on the complex or allosteric ligands that, by interacting with one co-receptor modify the function of the other co-receptor, or small molecules that can disrupt heteromeric complexes.
Taken together, the newly discovered aspects of dopamine receptor function might represent a breakthrough for the development of innovative drugs for the treatment of a variety of dopamine-related neurological and neuropsychiatric disorders.
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