SH3 Binding Domains in the Dopamine D4 Receptor

Oldenhof, John; Vickery, Ross G.; Anafi, Mordechai; J, Oak; A, Ray; Schoots, Oscar; Pawson, Tony; M, von Zastrow; Hh, Van Tol

doi:10.1021/bi981634+

Cited by 99 publications

(69 citation statements)

References 108 publications

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“…Epitope-tagged human DRD4 and human dopamine transporter (DAT) expressing vectors have been described elsewhere (24,50,51). Mutagenesis of methionine 345 of the DRD4 into alanine, serine, and threonine was done using standard molecular techniques (QuikChange TM ; Stratagene, La Jolla, CA).…”

Section: Methodsmentioning

confidence: 99%

Folding Efficiency Is Rate-limiting in Dopamine D4 Receptor Biogenesis

Craenenbroeck

Clark

Cox

et al. 2005

Journal of Biological Chemistry

101

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Dopamine receptors are G protein-coupled receptors that are critically involved in locomotion, reward, and cognitive processes. The D2 class of dopamine receptors (DRD2, -3, and -4) is the target for antipsychotic medication. DRD4 has been implicated in cognition, and genetic studies have found an association between a highly polymorphic repeat sequence in the human DRD4 coding region and attention deficit hyperactivity disorder. Using DRD4 as a model, we show that antipsychotics can function as potent pharmacological chaperones up-regulating receptor expression and can also rescue a non-functional DRD4 folding mutant. This chaperone-mediated up-regulation involves reduced degradation by the 26 S proteasome; likely via the stabilization of newly synthesized receptor in the endoplasmic reticulum. Dopamine itself can function as a chaperone when shuttled into the cell by means of the dopamine transporter. Furthermore, different repeat variants of DRD4 display differential sensitivity to this chaperone effect. These data suggest that folding efficiency may be rate-limiting for dopamine receptor biogenesis and that this efficiency differs between receptor variants. Consequently, the clinical profile of dopaminergic ligands, including antipsychotics, may include their ability to serve as pharmacological chaperones.

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Section: Methodsmentioning

confidence: 99%

Folding Efficiency Is Rate-limiting in Dopamine D4 Receptor Biogenesis

Craenenbroeck

Clark

Cox

et al. 2005

Journal of Biological Chemistry

101

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“…A full overview of Grb2 function is beyond the scope of this review; however, a number of interesting observations serve to illustrate the important involvement of this protein in many aspects of CNS function. Grb2 binds several brain proteins, including the dopamine receptors DRD3 and DRD4, 193,194 huntingtin 195 and PDE4D4. 196 Grb2 may also be involved in the pathology of Alzheimer's Disease through binding the amyloid precursor protein (APP) 197 and APP-processed fragments.…”

Section: Disc1 Interaction With Grb2mentioning

confidence: 99%

The DISC locus in psychiatric illness

et al. 2007

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The DISC locus is located at the breakpoint of a balanced t(1;11) chromosomal translocation in a large and unique Scottish family. This translocation segregates in a highly statistically significant manner with a broad diagnosis of psychiatric illness, including schizophrenia, bipolar disorder and major depression, as well as with a narrow diagnosis of schizophrenia alone. Two novel genes were identified at this locus and due to the high prevalence of schizophrenia in this family, they were named Disrupted-in-Schizophrenia-1 (DISC1) and Disrupted-in-Schizophrenia-2 (DISC2). DISC1 encodes a novel multifunctional scaffold protein, whereas DISC2 is a putative noncoding RNA gene antisense to DISC1. A number of independent genetic linkage and association studies in diverse populations support the original linkage findings in the Scottish family and genetic evidence now implicates the DISC locus in susceptibility to schizophrenia, schizoaffective disorder, bipolar disorder and major depression as well as various cognitive traits. Despite this, with the exception of the t(1;11) translocation, robust evidence for a functional variant(s) is still lacking and genetic heterogeneity is likely. Of the two genes identified at this locus, DISC1 has been prioritized as the most probable candidate susceptibility gene for psychiatric illness, as its protein sequence is directly disrupted by the translocation. Much research has been undertaken in recent years to elucidate the biological functions of the DISC1 protein and to further our understanding of how it contributes to the pathogenesis of schizophrenia. These data are the main subject of this review; however, the potential involvement of DISC2 in the pathogenesis of psychiatric illness is also discussed. A detailed picture of DISC1 function is now emerging, which encompasses roles in neurodevelopment, cytoskeletal function and cAMP signalling, and several DISC1 interactors have also been defined as independent genetic susceptibility factors for psychiatric illness. DISC1 is a hub protein in a multidimensional risk pathway for major mental illness, and studies of this pathway are opening up opportunities for a better understanding of causality and possible mechanisms of intervention. Molecular Psychiatry (2008) 13, 36-64; doi:10.1038/sj.mp.4002106; published online 2 October 2007 Keywords: schizophrenia; bipolar disorder; depression; DISC1; DISC2; mouse models Genetics of DISC1 discoverySt Clair et al. 1 first reported a Scottish family with a high loading of major mental illness, which cosegregates with a t(1;11) translocation. Long-term follow-up of this family over a period of 30 years has reported 87 family members, of whom 37 carry the translocation. 2 Of 29 individuals carrying the translocation, for whom psychiatric assessment was possible, 7 have a diagnosis of schizophrenia, 1 has a diagnosis of bipolar disorder and 10 cases of recurrent major depression were also reported. 2 Thus, 18 of 29 translocation carriers are diagnosed with major mental illness whereas none of...

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“…Besides short peptide sequences involved in G protein and arrestin binding, the remaining portions of these intracellular domains are presumably free to interact with other proteins. Using approaches such as co-immunoprecipitation and the yeast two-hybrid system, an increasing number of DRIPs are being identified [41][42][43]53,[68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83]. The confirmed DRIPs and their suggested functions are summarized in Table 1.…”

Section: Da Receptor-interacting Proteins (Drips)mentioning

confidence: 99%

Dopaminergic signaling in dendritic spines

Yao

Spealman

Zhang

2008

Biochemical Pharmacology

109

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Dopamine regulates movement, motivation, reward, and learning and is implicated in numerous neuropsychiatric and neurological disorders. The action of dopamine is mediated by a family of seven-transmembrane G protein-coupled receptors encoded by at least five dopamine receptor genes (D1, D2, D3, D4, and D5), some of which are major molecular targets for diverse neuropsychiatric medications. Dopamine receptors are present throughout the soma and dendrites of the neuron, but accumulating ultrastructural and biochemical evidence indicates that they are concentrated in dendritic spines, where most of the glutamatergic synapses are established. By modulating local channels, receptors, and signaling modules in spines, this unique population of postsynaptic receptors is strategically positioned to control the excitability and synaptic properties of spines and mediate both the tonic and phasic aspects of dopaminergic signaling with remarkable precision and versatility. The molecular mechanisms that underlie the trafficking, targeting, anchorage, and signaling of dopamine receptors in spines are, however, largely unknown. The present commentary focuses on this important subpopulation of postsynaptic dopamine receptors with emphases on recent molecular, biochemical, pharmacological, ultrastructural, and physiological studies that provide new insights about their regulatory mechanisms and unique roles in dopamine signaling. The Central Dopaminergic Systems: An OverviewDopamine (DA) is a prototypical slow neurotransmitter that plays pivotal roles in a variety of cognitive, motivational, neuroendocrine, and motor functions [1][2]. Two major groups of DAcontaining neurons in the mammalian brain reside in the substantia nigra pars compacta (SN) and the ventral tegmental area (VTA) [3]. SN neurons form the nigrostriatal pathway, which projects mainly to the dorsal part of striatum where they control postural reflexes and initiation of movements. VTA neurons give rise to two pathways: the mesolimbic pathway, which projects to the subcortical and limbic nuclei, and the mesocortical pathway, which projects mainly to the cingulate, entorhinal and medial prefrontal cortices. Dysfunction of dopaminergic transmission in these major pathways has been implicated in an array of neurological and neuropsychiatric disorders, including Parkinson's disease, Huntington's diseases, schizophrenia, attention-deficit hyperactivity disorder (ADHD), and drug addiction [1][2]. Drugs targeting dopaminergic mechanisms are widely used to manage these and other conditions.The action of DA is mediated by a family of seven-transmembrane G protein-coupled receptors (GPCRs) encoded by at least five DA receptor genes (D1, D2, D3, D4, and D5) in the mammalian brain [4]. These receptors are classified into two subfamilies, the D1-class and Corresponding author: Wei-Dong Yao, Ph.D., Department of Psychiatry, Harvard Medical School, Beth Israel Deaconess Medical Center, New England Primate Research Center, One Pine Hill Drive, P.O. Box 9102, Southborough,...

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SH3 Binding Domains in the Dopamine D4 Receptor

Cited by 99 publications

References 108 publications

Folding Efficiency Is Rate-limiting in Dopamine D4 Receptor Biogenesis

Folding Efficiency Is Rate-limiting in Dopamine D4 Receptor Biogenesis

The DISC locus in psychiatric illness

Dopaminergic signaling in dendritic spines

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