Zhuang X, Belluscio L, Hen R. G(olf)alpha mediates dopamine D1 receptor signaling. J Neurosci 20: RC91

Center for Neurobiology and Behavior, Columbia University, New York, New York 10032, USA.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.75). 09/2000; 20(16):RC91.
Source: PubMed

ABSTRACT It is generally assumed that the coupling of dopamine D1 receptors to adenylyl cyclase is mediated by the stimulatory GTP-binding protein G(s). However, the striatum contains little G(s)alpha subunit, whereas it expresses high levels of G(olf)alpha, a close relative of G(s)alpha that is also expressed in olfactory receptor neurons. We used G(olf)alpha knockout mice to examine the functional coupling of D1 receptors. We found that these mice showed no hyperlocomotor response to either the D1 agonist SKF-81297 or the psychostimulant cocaine. Moreover, G(olf)alpha knockout mice did not display cocaine-induced c-fos expression in the striatum. Finally, in the absence of G(olf)alpha, striatal D1 receptors have a decreased affinity for dopamine. Thus coupling to G(olf)alpha appears to mediate D1 signaling in the striatum.

Download full-text


Available from: Leonardo Belluscio, Aug 22, 2015
  • Source
    • "Among different mechanisms, several lines of evidence point to aberrant D1 receptor (D1R) signaling as a central event in the development of LID (Gerfen et al., 2002). In particular, increased D1R coupling to G alphaolf proteins (Aubert et al., 2005; Corvol et al., 2004; Herve et al., 1993) and adenylyl cyclase (AC) 5/6 (Rangel-Barajas et al., 2011), resulting in exaggerated cyclic AMP formation and overactivation of the cAMP-dependent protein kinase A (PKA) (Corvol et al., 2001; Picconi et al., 2003; Santini et al., 2007; Zhuang et al., 2000), has been demonstrated. These events result in the aberrant phosphorylation of downstream DA-and cAMP-regulated phosphorprotein 32 kDa (DARPP-32), leading to loss of depotentiation at cortico-striatal synapses (Picconi et al., 2003) and intensifying D1R-cAMP-mediated activation of Neurobiology of Disease 54 (2013) 339–348 Abbreviations: NMDAR, N-methyl-D-aspartate receptor; ITIM, immunoreceptor tyrosinebased inhibitory motif; STEP, striatal-enriched protein tyrosine phosphatase; MEK, mitogen-activated protein kinase kinase 1; MSK-1, mitogen and stress-activated kinase-1; TH, tyrosine hydroxylase; Shp-2, Src homology 2 domain (SH-2)-containing tyrosine phosphatise; CREB, cAMP response element-binding. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Prolonged L-3,4-dihydroxyphenylalanine (L-DOPA) administration, the gold standard therapy for Parkinson's disease (PD) is associated with serious motor complications, know as L-DOPA-induced dyskinesia (LID). One of the major molecular changes associated with LID is the increased activity of the extracellular signal-regulated kinases 1/2 (Erk1/2) signaling in the medium spiny neurons of the striatum induced by malfunctioning in the dopamine D1 receptor (D1R)-mediated transmission. We have previously established that in the striatum, activation of Shp-2, an intracellular tyrosine phosphatase associated with the D1R, is a requisite for the D1R to activate Erk1/2. In this study, we investigated the role of striatal D1R/Shp-2 complex in the molecular event underlying LID in the 6-OHDA-lesioned rat model of PD. We found that in hemiparkinsonian rats experiencing LID, the physiological interaction between D1R and Shp-2 in the striatum was preserved. In these animals, the chronic activation of D1R either by L-DOPA or by the selective D1R agonist SKF 38393 induced both dyskinesia and Shp-2/Erk1/2 activation. These effects were prevented by the selective D1R-antagonist SCH23390 suggesting the involvement of striatal D1R/Shp-2 complex, via Erk1/2 activation, in the molecular events underlying LID. Interestingly, we found that D1R-mediated Shp-2-Erk1/2 activation was persistently detected in the striatum of dyskinetic rats during L-DOPA washout, with a close correlation between LID severity and the extent of long term activation of both Shp-2 and Erk1/2. Taken together, our data show that in hemiparkinsonian rats developing dyskinesia, the aberrant phosphorylation of Shp-2 by D1R activation, represents an upstream molecular event leading to the persistent phosphorylation of Erk1/2 and therefore a novel therapeutic target to counteract LID development and maintenance during L-DOPA therapy.
    Neurobiology of Disease 01/2013; 54. DOI:10.1016/j.nbd.2013.01.005 · 5.20 Impact Factor
  • Source
    • "As previously mentioned, D1Rs and D2Rs mediate opposite regulations of cAMP signaling. In the striatum, activation of D1Rs in the direct MSNs leads to G olf -mediated stimulation of adenylyl cyclase, the enzyme responsible for the synthesis of cAMP (Zhuang et al., 2000; Herve et al., 2001). The ability of D1Rs to induce Gprotein-dependent activation of cAMP signaling promotes transmission at α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA; cf. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The basal ganglia are affected by several neuropsychiatric and neurodegenerative diseases, many of which are treated with drugs acting on the dopamine system. For instance, the loss of dopaminergic input to the striatum, which is the main pathological feature of Parkinson's disease, is counteracted by administering the dopamine precursor, L-DOPA. Furthermore, psychotic disorders, including schizophrenia, are treated with drugs that act as antagonists at the D2-type of dopamine receptor (D2R). The use of L-DOPA and typical antipsychotic drugs, such as haloperidol, is limited by the emergence of motor side-effects, particularly after prolonged use. Striatal medium spiny neurons (MSNs) represent an ideal tool to investigate the molecular changes implicated in these conditions. MSNs receive a large glutamatergic innervation from cortex, thalamus, and limbic structures, and are controlled by dopaminergic projections originating in the midbrain. There are two large populations of striatal MSNs, which differ based on their connectivity to the output nuclei of the basal ganglia and on their ability to express dopamine D1 receptors (D1Rs) or D2Rs. Administration of L-DOPA promotes cAMP signaling and activates the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) in the D1R-expressing MSNs, which form the striatonigral, or direct pathway. Conversely, haloperidol activates the cAMP/DARPP-32 cascade in D2R-expressing MSNs, which form the striatopallidal, or indirect pathway. This review describes the effects produced on downstream effector proteins by stimulation of cAMP/DARPP-32 signaling in these two groups of MSNs. Particular emphasis is given to the regulation of the GluR1 subunit of the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate glutamate receptor, the extracellular signal-regulated protein kinases 1 and 2, focusing on functional role and potential pathological relevance.
    Frontiers in Neuroanatomy 07/2011; 5:38. DOI:10.3389/fnana.2011.00038 · 4.18 Impact Factor
  • Source
    • "The monoamine dopamine modulates motor activity, cognition , mood, endocrine secretion, and a broad range of other physiological functions via actions at two families of G-protein-coupled receptors. D 1 -class receptors (D 1 and D 5 ) are principally coupled to stimulatory G␣-proteins and enhance the production of cAMP, whereas D 2 -class receptors (D 2 , D 3 , and D 4 subtypes) are primarily coupled to inhibitory G␣proteins and suppress the activity of adenylyl cyclase (Zhuang et al., 2000; Ahlgren-Beckendorf and Levant, 2004; Neve et al., 2004). D 2 receptors display a high degree of sequence similarity with D 3 receptors, and they share a predicted binding site for dopamine and synthetic ligands at the interface of transmembrane helices (Shi and Javitch, 2002). "
    [Show abstract] [Hide abstract]
    ABSTRACT: In view of the therapeutic importance of dopamine D(3) and D(2) receptors, there remains considerable interest in novel ligands. Herein, we show that the tetrahydroisoquinoline 1H-indole-2-carboxylic acid {4-[2-(cyano-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-cyclohexyl}-amide (SB269,652) behaves as an atypical, allosteric antagonist at D(3) and D(2) receptors. Accordingly, SB269,652 potently (low nanomolar range) abolished specific binding of [(3)H]nemanopride and [(3)H]spiperone to Chinese hamster ovary-transfected D(3) receptors when radioligands were used at 0.2 and 0.5 nM, respectively. However, even at high concentrations (5 μM), SB269,652 only submaximally inhibited the specific binding of these radioligands when they were employed at 10-fold higher concentrations. By analogy, although SB269,652 potently blocked D(3) receptor-mediated activation of Gα(i3) and phosphorylation of extracellular-signal-regulated kinase (ERK)1/2, when concentrations of dopamine were increased by 10-fold, from 1 μM to 10 μM, SB269,652 only submaximally inhibited dopamine-induced stimulation of Gα(i3). SB269,652 (up to 10 μM) only weakly and partially (by approximately 20-30%) inhibited radioligand binding to D(2) receptors. Likewise, SB269,652 only submaximally suppressed D(2) receptor-mediated stimulation of Gα(i3) and Gα(qi5) (detected with the aequorin assay) and phosphorylation of ERK1/2 and Akt. Furthermore, SB269,652 only partially (35%) inhibited the dopamine-induced recruitment of β-arrestin2 to D(2) receptors. Finally, Schild analysis using Gα(i3) assays, and studies of radioligand association and dissociation kinetics, supported allosteric actions of SB269,652 at D(3) and D(2) receptors.
    Molecular pharmacology 11/2010; 78(5):925-34. DOI:10.1124/mol.110.065755 · 4.12 Impact Factor
Show more