Evidence that a single nucleotide polymorphism in the promoter of the G protein receptor kinase 3 gene is associated with bipolar disorder

Barrett, Thomas B.; Hauger, Richard L.; Kennedy, James L.; Sadovnick, A. Dessa; Remick, Ronald A.; Keck, Paul E.; McElroy, Susan L.; Alexander, Madeline; Shaw, Sarah H.; Kelsoe, John R.

doi:10.1038/sj.mp.4001268

Cited by 108 publications

(56 citation statements)

References 32 publications

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“…Collectively, these observations suggest that the defective GRK3 mRNA expression in P3 cells arises from an impaired synthesis, either directly due to a polymorphism in transcriptional regulatory regions or indirectly due to the altered expression of a transcription factor that modulates GRK3 expression. Several SNPs were identified in the putative promoter region of GRK3, which may affect the regulation of gene expression, and were associated with bipolar disorder in families of northern European Caucasian ancestry (44,45). We did not identify any specific SNP in the minimal putative promoter region of GRK3 in P3 cells.…”

Section: Figurementioning

confidence: 79%

Leukocyte analysis from WHIM syndrome patients reveals a pivotal role for GRK3 in CXCR4 signaling

Balabanian¹,

Levoye²,

Klemm³

et al. 2008

J. Clin. Invest.

105

133

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Leukocytes from individuals with warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, a rare immunodeficiency, and bearing a wild-type CXCR4 ORF (WHIM WT ) display impaired CXCR4 internalization and desensitization upon exposure to CXCL12. The resulting enhanced CXCR4-dependent responses, including chemotaxis, probably impair leukocyte trafficking and account for the immunohematologic clinical manifestations of WHIM syndrome. We provided here evidence that GPCR kinase-3 (GRK3) specifically regulates CXCL12-promoted internalization and desensitization of CXCR4. GRK3-silenced control cells displayed altered CXCR4 attenuation and enhanced chemotaxis, as did WHIM WT cells. These findings identified GRK3 as a negative regulator of CXCL12-induced chemotaxis and as a candidate responsible for CXCR4 dysfunction in WHIM WT leukocytes. Consistent with this, we showed that GRK3 overexpression in both leukocytes and skin fibroblasts from 2 unrelated WHIM WT patients restored CXCL12-induced internalization and desensitization of CXCR4 and normalized chemotaxis. Moreover, we found in cells derived from one patient a profound and selective decrease in GRK3 products that probably resulted from defective mRNA synthesis. Taken together, these results have revealed a pivotal role for GRK3 in regulating CXCR4 attenuation and have provided a mechanistic link between the GRK3 pathway and the CXCR4-related WHIM WT disorder.

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Section: Figurementioning

confidence: 79%

Leukocyte analysis from WHIM syndrome patients reveals a pivotal role for GRK3 in CXCR4 signaling

Balabanian¹,

Levoye²,

Klemm³

et al. 2008

J. Clin. Invest.

105

133

View full text Add to dashboard Cite

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“…The gene for regulator of G-protein signaling 4 (RGS4) was initially brought into attention by a microarray study and recently reported to be associated with schizophrenia. 30 Selecting candidates based on expression data also led to the detection of associations of Gprotein-coupled receptor kinase3 (GRK3) 31 and other promising gene 32 with bipolar disorder. Altered expression level of G protein AS and AI2 subunits (GNAS, GNAI2) in the post-mortem brains from bipolar or lithium receiving subjects has also been reported, 33 although variants in the former gene are not apparently associated with bipolar disorder.…”

Section: Neurotransmission Systemsmentioning

confidence: 99%

Genetic tests of biologic systems in affective disorders

et al. 2005

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To liberate candidate gene analyses from criticisms of inexhaustiveness of examination of specific candidate genes, or incompleteness in the choice of candidate genes to study for specific neurobiological pathways, study of sizeable sets of genes pertinent to each putative pathophysiological pathway is required. For many years, genes have been tested in a 'one by one' manner for association with major affective disorders, primarily bipolar illness. However, it is conceivable that not individual genes but abnormalities in several genes within a system or in several neuronal, neural, or hormonal systems are implicated in the functional hypotheses for etiology of affective disorders. Compilation of candidate genes for entire pathways is a challenge, but can reasonably be carried out for the major affective disorders as discussed here. We present here five groupings of genes implicated by neuropharmacological and other evidence, which suggest 252 candidate genes worth examining. Inexhaustiveness of gene interrogation would apply to many studies in which only one polymorphism per gene is analyzed. In contrast to whole-genome association studies, a study of a limited number of candidate genes can readily exploit information on genomic sequence variations obtained from databases and/or resequencing, and has an advantage of not having the complication of an extremely stringent statistical criterion for association. Molecular Psychiatry (2005) 10, 719-740.

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“…Recent reports describing the putative promoter region of the GRK3 gene have suggested the presence of binding sites for the transcription factors, Sp-1 and Ap-2, in the GRK3 promoter region (Barrett et al, 2003). Therefore, we examined the nuclear translocation of these transcription factors in response to EPI (0.3 M) treatment.…”

Section: Regulation Of Grk3 Expression 53mentioning

confidence: 99%

“…GRK2 promoter-luciferase reporter constructs have demonstrated that phorbol esters, ␣ 1 -AR agonists, and serum stimulation (Ramos-Ruiz et al, 2000;Theilade et al, 2005) increase GRK2 expression at the transcriptional level. However, there are relatively few reports of the selective increase in GRK3 expression (Dautzenberg and Hauger, 2001;Dautzenberg et al, 2002), and the GRK3 gene promoter has not been characterized but is predicted to lie in the genomic region immediately 5Ј to exon 1 (Barrett et al, 2003).…”

mentioning

confidence: 99%

Extracellular Signal-Regulated Kinase 1/2-Mediated Transcriptional Regulation of G-Protein-Coupled Receptor Kinase 3 Expression in Neuronal Cells

Salim

Standifer²,

Eikenburg³

2007

J Pharmacol Exp Ther

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Relatively small changes in G-protein-coupled receptor kinase (GRK) 3 expression (ϳ2-fold) profoundly affect ␣ 2 -adrenergic receptor (AR) function and preferentially regulate neuronal ␣ 2A -and ␣ 2B -AR signaling. In the present study, we provide evidence that epinephrine (EPI)-induced up-regulation of GRK3 protein expression in two neuronal cell lines, BE(2)-C cells (endogenously express ␣ 2A -and ␤ 2 -AR) and BN17 cells [endogenously express ␣ 2B (NG108) and transfected to express ␤ 2 -AR] is due in part to increased GRK3 gene expression. In both cell lines, the increase in GRK3 transcription occurred via an extracellular signal-regulated kinase (ERK) 1/2-dependent mechanism because the increase in GRK3 mRNA is eliminated in the presence of the mitogen-activated protein kinase/ERK kinase 1/2 inhibitor, U0126 [1,4-diamino-2,3-dicyano-1,4-bis (2-amino phenylthiobutadiene)]. EPI-induced GRK3 mRNA upregulation also is prevented in the presence of propranolol or phentolamine. Moreover, GRK3 mRNA did not increase in response to EPI treatment in NG108 cells (endogenously express ␣ 2B -AR with no ␤ 2 -AR). Both these results suggest that simultaneous activation of ␣ 2 -and ␤ 2 -AR by EPI is required for the ERK1/2-dependent increase in GRK3 mRNA. The EPI-induced increase in GRK3 mRNA was unaffected in the presence of the protein kinase C inhibitor, chelerythrine chloride. Finally, EPI treatment resulted in increased nuclear translocation and accumulation of the transcription factors, Sp-1 and Ap-2, in BE(2)-C cells. Taken together, our results demonstrate the involvement of the ERK1/2 pathway in selective up-regulation of GRK3 mRNA expression, possibly via activation of Sp-1 and Ap-2 transcription factors in neuronal cells.G-protein-coupled receptor kinases (GRKs) specifically interact with agonist-occupied G-protein-coupled receptors (GPCRs) to mediate receptor phosphorylation. This phosphorylation increases the affinity of the receptor for arrestin, and receptor/G-protein interaction is inhibited even in the presence of agonist. The resulting rapid loss of receptor responsiveness is termed desensitization and in many instances is followed by the removal of the receptor from the plasma membrane via clathrin-mediated endocytosis (Penn et al

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Evidence that a single nucleotide polymorphism in the promoter of the G protein receptor kinase 3 gene is associated with bipolar disorder

Cited by 108 publications

References 32 publications

Leukocyte analysis from WHIM syndrome patients reveals a pivotal role for GRK3 in CXCR4 signaling

Leukocyte analysis from WHIM syndrome patients reveals a pivotal role for GRK3 in CXCR4 signaling

Genetic tests of biologic systems in affective disorders

Extracellular Signal-Regulated Kinase 1/2-Mediated Transcriptional Regulation of G-Protein-Coupled Receptor Kinase 3 Expression in Neuronal Cells

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