Together with G protein-coupled receptor (GPCR) kinases (GRKs) and ␤-arrestins, RGS proteins are the major family of molecules that control the signaling of GPCRs. The expression pattern of one of these RGS family members, RGS9-2, coincides with that of the dopamine D 3 receptor (D 3 R) in the brain, and in vivo studies have shown that RGS9-2 regulates the signaling of D2-like receptors. In this study, ␤-arrestin2 was found to be required for scaffolding of the intricate interactions among the dishevelled-EGL10-pleckstrin (DEP) domain of RGS9-2, G␤5, R7-binding protein (R7BP), and D 3 R. The DEP domain of RGS9-2, under the permission of ␤-arrestin2, inhibited the signaling of D 3 R in collaboration with G␤5. ␤-Arrestin2 competed with R7BP and G␤5 so that RGS9-2 is placed in the cytosolic region in an open conformation which is able to inhibit the signaling of GPCRs. The affinity of the receptor protein for ␤-arrestin2 was a critical factor that determined the selectivity of RGS9-2 for the receptor it regulates. These results show that ␤-arrestins function not only as mediators of receptor-G protein uncoupling and initiators of receptor endocytosis but also as scaffolding proteins that control and coordinate the inhibitory effects of RGS proteins on the signaling of certain GPCRs.The regulation of G protein-coupled receptors (GPCRs) involves various cellular events in different time frames, and the detailed regulatory mechanism can be unique for each receptor type and the signal it mediates. Much of our knowledge concerning the molecular basis of homologous desensitization of GPCRs is derived from studies of the ␤ 2 -adrenergic receptor (␤ 2 AR), in which GPCR kinases (GRKs) and ␤-arrestins play central roles. According to this working model, GRK-mediated receptor phosphorylation, followed by the association of ␤-arrestin, causes uncoupling of the GPCR from the G protein (16,18,30). However, the detailed molecular mechanism of this uncoupling of receptors from the G protein is unclear, aside from the simple idea that ␤-arrestins could physically interfere with the interaction between the receptor and G protein.Upon agonist binding, GPCRs stimulate the conversion of the inactive heterotrimeric GTP-binding protein GDP-G␣␤␥ to GTP-G␣ and G␤␥. The duration of the active state of the G protein, GTP-G␣, is regulated by two different cellular components, the weak GTPase activity of G␣ itself and the catalytic activity of GTPase-activating proteins (GAPs). Regulators of G protein signaling (RGS) act as GAPs for the heterotrimeric G protein ␣ subunit (49). More than 30 RGS proteins have been discovered over the last decade, and they are divided into 8 subfamilies (11,26,52).Among these RGS proteins, RGS2, RGS4, and RGS9-2 are known to be mutually related to the dopaminergic nervous system. It is known that the expression of the genes for RGS2 and RGS4 changes in response to dopaminergic stimulation (43, 44); however, the roles of RGS2 and RGS4 in the signaling and intracellular trafficking of D 2 R and D 3 R have not been...

Intensive glucose control increases the all-cause mortality in type 2 diabetes mellitus (T2DM); however, the underlying mechanisms remain unclear. We hypothesized that strict diet control to achieve euglycemia in diabetes damages major organs, increasing the mortality risk. To evaluate effects on major organs when euglycemia is obtained by diet control, we generated a model of end-stage T2DM in 13-week-old Sprague-Dawley rats by subtotal pancreatectomy, followed by ad libitum feeding for 5 weeks. We divided these rats into two groups and for the subsequent 6 weeks provided ad libitum feeding to half (AL, n=12) and a calorie-controlled diet to the other half (R, n=12). To avoid hypoglycemia, the degree of calorie restriction in the R group was isocaloric (g per kg body weight per day) compared with a sham-operated control group (C, n=12). During the 6-week diet control period, AL rats ate three times more than rats in the C or R groups, developing hyperglycemia with renal hyperplasia. R group achieved euglycemia but lost overall body weight significantly compared with the C or AL group (49 or 22%, respectively), heart weight (39 or 23%, respectively) and liver weight (50 or 46%, respectively). Autophagy levels in the heart and liver were the highest in the R group (P<0.01), which also had the lowest pAkt/Akt levels among the groups (P<0.05 in the heart; P<0.01 in the liver). In conclusion, glycemic control achieved by diet control can prevent hyperglycemia-induced renal hyperplasia in diabetes but may be deleterious even at isocaloric rate when insulin is deficient because of significant loss of heart and liver mass via increased autophagy.

The KMT2 (MLL) family of proteins, including the major histone H3K4 methyltransferase found in mammals, exists as large complexes with common subunit proteins and exhibits enzymatic activity. SMYD, another H3K4 methyltransferase, and SET7/9 proteins catalyze the methylation of several non-histone targets, in addition to histone H3K4 residues. Despite these structural and functional commonalities, H3K4 methyltransferase proteins have specificity for their target genes and play a role in the development of various cancers as well as in drug resistance. In this review, we examine the overall role of histone H3K4 methyltransferase in the development of various cancers and in the progression of drug resistance. Compounds that inhibit protein–protein interactions between KMT2 family proteins and their common subunits or the activity of SMYD and SET7/9 are continuously being developed for the treatment of acute leukemia, triple-negative breast cancer, and castration-resistant prostate cancer. These H3K4 methyltransferase inhibitors, either alone or in combination with other drugs, are expected to play a role in overcoming drug resistance in leukemia and various solid cancers.

In previous studies we have demonstrated that the γ-aminobutryic acid-A (GABA-A) receptor antagonist oroxylin A has an awakening effect and it also represses ADHD-like behaviors (hyperactivity, impulsivity and inattention) in the spontaneously hypertensive rat (SHR) model of attention-deficit hyperactivity disorder (ADHD). We hypothesized that the effects of oroxylin A were exerted via the GABA-A receptor given the important role of the GABAergic system in ADHD. However, it is possible that aside from the GABAergic system, oroxylin A may influence other systems especially those implicated in ADHD (e.g. DAergic, etc.). To test this hypothesis, we evaluated the effects of GABA agonist, or dopamine (DA) antagonist in oroxylin A-induced alleviation of ADHD-like behaviors in SHR. SHR showed inattention and impulsivity as measured by the Y-maze and the electro-foot shock aversive water drinking tests, respectively. Oroxylin A significantly improved these behaviors, furthermore, its effect on SHR impulsivity was attenuated by haloperidol, a DA antagonist, but not by baicalein, an agonist of the GABA-A receptor. In vitro studies showed that oroxylin A inhibited DA uptake similar to methylphenidate, a dopamine transporter blocker, but did not influence norepinephrine uptake unlike atomoxetine, a selective NE reuptake inhibitor. Collectively, the present findings suggest that oroxylin A improves ADHD-like behaviors in SHR via enhancement of DA neurotransmission and not modulation of GABA pathway as previously reported. Importantly, the present study indicates the potential therapeutic value of oroxylin A in the treatment of ADHD.

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