Expression of the D3 Dopamine Receptor Gene and a Novel Variant Transcript Generated by Alternative Splicing in Human Peripheral Blood Lymphocytes

Nagai, Yoshitaka; Ueno, S.; Saeki, Yoshinaga; Soga, Fumihisa; Yanagihara, Takehiko

doi:10.1006/bbrc.1993.1829

Cited by 81 publications

(36 citation statements)

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“…Five additional alternatively spliced variants have also been described, which do not bind dopamine, and are believed to function instead through the regulation of receptor dimerization (Snyder et al, 1991). These include D3 (TM3-del) Snyder et al, 1991), D3 (TM4-del) (Nagai et al, 1993), D3 (O2-del) , rD3in (Pagliusi et al, 1993), and D3nf (Schmauss et al, 1993;Liu et al, 1994b). D3nf is the best characterized of the non-dopamine-binding splice variants.…”

Section: D3 Dopamine Receptor Alternative Splicingmentioning

confidence: 99%

Behavioral Sensitization, Alternative Splicing, and D3 Dopamine Receptor-Mediated Inhibitory Function

Richtand

2006

Neuropsychopharmacol

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Behavioral sensitization, the progressive and enduring augmentation of certain behaviors following repetitive drug use, alters rodent locomotion in a long-standing manner. The same dopamine pathways playing an important role in drug dependence and psychosis also play a critical role in sensitization. Individual dopamine receptor subtypes have markedly different functional responses to stimulation, with D3 dopamine receptor stimulation inhibiting rodent locomotion. The D3 receptor has highest affinity of the dopamine receptor subtypes for dopamine, and is occupied to a greater degree following stimulant drug administration. D3 receptor activity may be regulated through the expression of an alternatively spliced, truncated receptor isoform (termed 'D3nf') altering receptor localization and function via dimerization with the full-length subunit. The expected physiological response to repetitive drug administration is tolerance. Tolerance of D3 receptor inhibition of locomotion would contribute to sensitization to stimulant drugs. We hypothesize that repetitive D3 receptor stimulation contributes to the development of behavioral sensitization through decreased responsivity of D3-receptor-mediated locomotor inhibition. Increased D3nf expression may direct altered receptor localization and subsequent release of D3-receptormediated inhibition, contributing to the expression of sensitization. These hypotheses follow directly from the affinities of the receptor subtypes for dopamine; dopamine concentrations following stimulant administration; the effects of individual dopamine receptor subtype stimulation on locomotion; and the expected homeostatic response of the system to perturbation by drug. Clarifying these mechanisms underlying sensitization may suggest new interventions for neuropsychiatric conditions in which dopamine plays an important role, including psychosis, drug dependence, and Parkinson's disease. This information may also elucidate a previously unrecognized mechanism regulating receptor trafficking and desensitization.

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Section: D3 Dopamine Receptor Alternative Splicingmentioning

confidence: 99%

Behavioral Sensitization, Alternative Splicing, and D3 Dopamine Receptor-Mediated Inhibitory Function

Richtand

2006

Neuropsychopharmacol

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“…Substances detected in human lymphocytes include, among others, mRNAs corresponding to the kappa opioid receptor (Takahashi et al, 1992), an astroglial marker (Riol et al, 1997), and the dopaminergic receptors D3 (Nagai et al, 1993), D4 (Bondy et al, 1996) and D5 (Takahashi et al, 1992), which have a known function in the nervous sys-20…”

Section: Discussionmentioning

confidence: 99%

“…It is noteworthy that genes which have an important function in other tissues have been found to be lowly expressed in lymphocytes and without a known function. Such is the case of the dystrophin gene which plays a role in muscles (Chelly et al, 1988), of dopaminergic receptors in the brain (Bondy et al 1996;Nagai et al 1993;Takahashi et al 1992), and of glial protein RNAs, in the peripheral nervous system (Riol et al 1997). …”

Section: Introductionmentioning

confidence: 99%

Expression in normals and in subjects with schizophrenia of a novel gene fragment originally isolated from monozygotic twins discordant for schizophrenia

et al. 2004

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Differentially expressed clones from subtracted cDNA libraries of a pair of monozygotic twins discordant for schizophrenia have been reported in the literature. The clones were expressed in lymphocytes from the healthy twin, but not from the schizophrenic twin. In the current study, we assessed the expression of one of these clones, oksc12b, in 10 normal controls and in 10 patients who met DSM-IV criteria for schizophrenia and had never received neuroleptic medication. We hypothesized that this clone would be differentially expressed in normal controls and in the schizophrenic patients, and that its expression could be a peripheral marker of the disease. Lymphocytes were isolated and total RNA was purified, reverse-transcribed, and quantified by two PCR methods. In the first PCR assay, oksc12b expression was measured relative to beta-actin gene expression. The second PCR assay consisted of a competitive procedure using a heterologous DNA internal standard. Neither method confirmed any difference in oksc12b expression between schizophrenic patients and normal controls. Subtypes of schizophrenia or the general heterogeneity of this syndrome may explain the discrepancy found. It is also possible that the differentially expressed clones are present in discordant monozygotic twins, but not in other patients.

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“…Although the full significance of this finding is not yet understood (see Macciardi et al, 1994), it might suggest a contributory etiological role of the D 3 receptor in schizophrenia. Furthermore, a postmortem study showed that D 3 mRNA was lost in certain cortical regions of brains obtained from patients with chronic schizophrenia, whereas a truncated D 3 -like mRNA (named D 3nf ) could readily be detected in the same anatomic regions (Schmauss et al, 1993).Several different truncated dopamine D 3 -like mRNAs that do not encode G-protein-coupled receptors have been identified (Giros et al, 1991;Snyder et al, 1991;Nagai et al, 1993;Schmauss et al, 1993). Their function is unknown.…”

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confidence: 99%

“…Several different truncated dopamine D 3 -like mRNAs that do not encode G-protein-coupled receptors have been identified (Giros et al, 1991;Snyder et al, 1991;Nagai et al, 1993;Schmauss et al, 1993). Their function is unknown.…”

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confidence: 99%

Enhanced Cleavage of an Atypical Intron of Dopamine D₃-Receptor Pre-mRNA in Chronic Schizophrenia

Schmauss

1996

J. Neurosci.

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The D 2 -class of dopamine receptors (D 2 , D 3 , and D 4 ) is a target for typical and atypical neuroleptic drugs. They have been considered, therefore, as factors that may contribute to the pathophysiology of psychotic disorders. Interestingly, in cortical brain tissues obtained postmortem form patients with chronic schizophrenia D 3 mRNA was found to be significantly lower than in the corresponding anatomic regions of controls. Because the expression of a truncated D 3 -like mRNA (named D 3nf ) appeared to be unaffected in schizophrenic brains, these findings suggest the possibility that the loss of D 3 mRNA results from an abnormal splicing of D 3 pre-mRNA in schizophrenia that is accompanied by an increased accumulation of the truncated D 3nf mRNA. To test this, three approaches were taken. (1) (Bunzow et al., 1988;Dal Toso et al., 1989;Grandy et al., 1989;Giros et al., 1989;Monsma et al., 1989), D 3 (Sokoloff et al., 1990), and D 4 (Van Tol et al., 1991), are targets for drugs with antipsychotic efficacy and have been repeatedly suggested as factors in the pathophysiology of schizophrenia. Although there is at present no evidence of linkage between the D 3 gene and schizophrenia, several studies suggest that a distinct polymorphism in the first coding exon of the D 3 gene increases the susceptibility to schizophrenia (Crocq et al., 1992;Mant et al., 1994;Asherson et al., 1996;Shaikh et al., 1996). Although the full significance of this finding is not yet understood (see Macciardi et al., 1994), it might suggest a contributory etiological role of the D 3 receptor in schizophrenia. Furthermore, a postmortem study showed that D 3 mRNA was lost in certain cortical regions of brains obtained from patients with chronic schizophrenia, whereas a truncated D 3 -like mRNA (named D 3nf ) could readily be detected in the same anatomic regions (Schmauss et al., 1993).Several different truncated dopamine D 3 -like mRNAs that do not encode G-protein-coupled receptors have been identified (Giros et al., 1991;Snyder et al., 1991;Nagai et al., 1993;Schmauss et al., 1993). Their function is unknown. The longest of these mRNAs, named D 3nf , results from a deletion of 98 nt that constitute the C-terminal region of the putative third cytoplasmic domain of the D 3 receptor and, therefore, encodes a D 3 -like protein with a different C terminus (Schmauss et al., 1993;Liu et al., 1994). In human brain, D 3nf mRNA was shown to be abundantly expressed and also translated into protein (Liu et al., 1994), suggesting that D 3nf mRNA does not result from an RNA processing error. Another interesting observation is that D 3nf mRNA was expressed in certain neocortical regions of brains obtained from patients with chronic schizophrenia, regions in which the expression of D 3 mRNA was found to be lost (Schmauss et al., 1993).The human genome contains a single, intron-containing D 3 -encoded gene in which the 98 nt that are deleted in D 3nf are embedded within a large continuous exon (Liu et al., 1994). Thus, to generate D 3nf mRNA via alter...

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Expression of the D3 Dopamine Receptor Gene and a Novel Variant Transcript Generated by Alternative Splicing in Human Peripheral Blood Lymphocytes

Cited by 81 publications

References 0 publications

Behavioral Sensitization, Alternative Splicing, and D3 Dopamine Receptor-Mediated Inhibitory Function

Behavioral Sensitization, Alternative Splicing, and D3 Dopamine Receptor-Mediated Inhibitory Function

Expression in normals and in subjects with schizophrenia of a novel gene fragment originally isolated from monozygotic twins discordant for schizophrenia

Enhanced Cleavage of an Atypical Intron of Dopamine D₃-Receptor Pre-mRNA in Chronic Schizophrenia

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Expression of the D3 Dopamine Receptor Gene and a Novel Variant Transcript Generated by Alternative Splicing in Human Peripheral Blood Lymphocytes

Cited by 81 publications

References 0 publications

Behavioral Sensitization, Alternative Splicing, and D3 Dopamine Receptor-Mediated Inhibitory Function

Behavioral Sensitization, Alternative Splicing, and D3 Dopamine Receptor-Mediated Inhibitory Function

Expression in normals and in subjects with schizophrenia of a novel gene fragment originally isolated from monozygotic twins discordant for schizophrenia

Enhanced Cleavage of an Atypical Intron of Dopamine D3-Receptor Pre-mRNA in Chronic Schizophrenia

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Enhanced Cleavage of an Atypical Intron of Dopamine D₃-Receptor Pre-mRNA in Chronic Schizophrenia