Disease relevance of ADRBK2

• These experiments demonstrate that GRK3 plays an important role in the homologous desensitization of retinoblastoma PAC(1) receptors, whereas PKC, but not PKA, contributes to the heterologous desensitization of retinoblastoma PAC(1) receptors [1].

Psychiatry related information on ADRBK2

• A polymorphism in the promoter region of the ADRBK2 was reported to be associated with bipolar disorder [2].

High impact information on ADRBK2

• Studies of the details and consequences of these mechanisms have focused heavily on the original beta-adrenoceptor kinase (beta-ARK) family (GRK2 and GRK3) and, in particular, on phosphorylation-dependent recruitment of adaptor proteins such as the beta-arrestins [3].
• The beta-adrenergic receptor kinases (GRK2 and GRK3) associate with heterotrimeric G protein beta gamma-subunits, released upon receptor activation of G proteins, for membrane anchorage [4].
• In contrast, ERK1/2 activation by fentanyl was not evident in neurons from GRK3(-/-) mice or neurons pretreated with small inhibitory RNA for arrestin3 [5].
• In addition, activation of ERK1/2 by fentanyl and morphine was rescued in GRK3(-/-) neurons following transfection with dominant positive arrestin3-(R170E) [5].
• Consistent with these results, in vitro phosphorylation by GRK3 of KOR isolated from tolerant mice resulted in 46 +/- 7% less (32)P incorporation than in KOR isolated from untreated mice [6].

Chemical compound and disease context of ADRBK2

• CONCLUSIONS: These results show that chronically administered Li+ and CBZ, but not VPA, increase the translocation of GRK3 from cytosol to membrane, possibly correcting supersensitivity of GPCRs in bipolar disorder [7].

Biological context of ADRBK2

• Coexpression of beta-adrenergic receptor kinase (betaARK) 1 (GRK2) or 2 (GRK3) could increase epinephrine-induced phosphorylation of the wild type alpha1BAR above basal as compared to that of the receptor expressed alone [8].
• To identify possible functional mutations in GRK3, we sequenced the putative promoter region, all 21 exons, and intronic sequence flanking each exon, in 14-22 individuals with BPD [9].
• Two independent family sets yielded lod scores suggestive of linkage at markers in this region near the gene G protein receptor kinase 3 (GRK3) [9].
• This lower threshold for down-regulation is associated with alpha(2B)- and beta(2)-AR dependent up-regulation of GRK3 expression [10].
• (7) We conclude that chronic treatment with modest levels of ADR produces alpha(2A)-AR desensitization by mechanisms that involve up-regulation of GRK3 and down-regulation of alpha(2A)-AR levels through interactions with the beta(2)-AR [11].

Anatomical context of ADRBK2

• Microinjection of GRK2/3-specific mAbs into chicken sensory neurons, which have been shown to express a GRK3-like protein, abolishes desensitization of the alpha2AR-mediated calcium current inhibition [12].
• In oocytes expressing GRK5 instead of GRK3, both [D-Ala2,N-MePhe4, Gly-ol5]enkephalin and fentanyl, but not morphine, produced desensitization of MOR-activated potassium conductance [13].
• Using immunohistochemistry, both GRK2 and GRK3 were found to be expressed in detrusor smooth muscle cells [14].
• These results indicate that in H2r-transfected COS-7 cells, exposure to an agonist caused desensitization controlled by H2r phosphorylation via GRK2 and GRK3 [15].
• However, in the same cell lines under the same conditions, overexpression of beta-adrenergic receptor kinase 2 and beta-arrestin 2 accelerated the rate of DPDPE- but not DAMGO-induced receptor desensitization [16].

Associations of ADRBK2 with chemical compounds

• Treatment with opioids of high efficacy, either [D-Ala2,N-MePhe4,Gly-ol5]-enkephalin, fentanyl, or sufentanyl, produced a GRK3- and beta-arr 2-dependent reduction in response in <20 min, whereas treatment with the partial agonist morphine produced receptor desensitization at a significantly slower rate [13].
• Threonine 180 is required for G-protein-coupled receptor kinase 3- and beta-arrestin 2-mediated desensitization of the mu-opioid receptor in Xenopus oocytes [17].
• Cells expressing the rat D1A receptor with GRK2 and GRK3 displayed a rightward shift of the dopamine dose-response curve with little effect on the maximal activation when compared with cells expressing the receptor alone [18].
• Overexpression of GRK2, but not GRK3, enhanced PTH-stimulated receptor phosphorylation, and this phosphorylation was abolished by alanine mutagenesis of residues 483, 485, 486, 489, 495, and 498 [19].
• RESULTS: Chronic Li+ (24%) and CBZ (44%) significantly increased GRK3 in the membrane but not cytosol fractions [7].

Enzymatic interactions of ADRBK2

• We hypothesize that GRK3 upregulation may be a cellular negative feedback process directed at maximizing CRF(1) receptor desensitization by heightening GRK3 phosphorylating capacity during prolonged exposure to high CRF [20].

Regulatory relationships of ADRBK2

• Conversely, antibody-mediated inhibition of endogenous GRK2 and GRK3 significantly inhibited C3aR phosphorylation in permeabilized cells [21].
• (5) Chronic ADR treatment produced a significant increase in GRK3 levels and this was blocked by propranolol or GRK2/3 antisense DNA treatment [11].
• In preliminary experiments, retinoblastoma GRK3 protein expression became upregulated during a 48-h CRF exposure [20].
• Coexpression with either GRK3 or arr3 individually did not significantly enhance desensitization of responses evoked by wild type MOR activation [17].
• In addition, direct stimulation of G protein activation of phospholipase C (by AlF4(-)) was inhibited in GRK3- but not GRK6-overexpressing cells [22].

Other interactions of ADRBK2

• Thus, mu-opioid agonists produced significant receptor desensitization, mediated by either GRK3 or GRK5, at a rate dependent on agonist efficacy [13].
• ATP stimulates GRK-3 phosphorylation and beta-arrestin-2-dependent internalization of P2X7 receptor [23].
• Antibodies to GRK2, GRK3 and GRK4 were used to confirm the presence of the protein product in the human urinary bladder using immunohistochemical staining and the western blotting technique [24].
• Because GRK3 requires activation and membrane targeting by free G protein betagamma subunits released after agonist-mediated activation of G proteins, a low efficacy agonist such as morphine may produce weak receptor desensitization as a consequence of poor GRK3 activation [13].
• GRK 4 and GRK 6 did not alter dose-dependent signaling, and GRK 3 was intermediate in effect [25].

Analytical, diagnostic and therapeutic context of ADRBK2

• The GRK2 and GRK3 transcripts were detected by RT-PCR [14].
• We have also previously shown GRK3 expression to be induced by amphetamine in an animal model of mania using microarray-based expression profiling [9].
• Molecular cloning, functional expression and mRNA analysis of human beta-adrenergic receptor kinase 2 [26].

References