Relationship between 5-hydroxytryptamine 1A receptor and G-protein β3 subunit polymorphisms and post-stroke depression / 中华神经科杂志

Objective To assess whether 5-HTR1A C( - 1019) G and GNβ3 C825T gene polymorphisms are associated with post-stroke depression (PSD) and explore the genetic mechanism of the pathogenesis of post-stroke depression. Methods All 159 patients with first stroke were divided into the PSD group and the control group according to HAMD scores. Their genotypes were determined with polymerase chain reaction and allele-specific restriction enzyme analysis. Results The frequency of 5-HTR1A (-1019) GG genotype(8/53,15. 1% ), G allele (44/106,41.5%)and GNβ3 825T allele(68/106,64. 2% ) were significantly higher in the post-stroke depression group than in the controls (5/106,4.7% ;35/212, 16. 5%; 113/212, 53.3%; ×2 = 23.204, 23. 655, 3. 392, all P ＜ 0. 05 ). Combined genotype analysis showed that individuals with both 5-HTR1A ( - 1019) G and GNβ3 825T allele ( OR =4. 980,95% CI 2. 429-10. 210,P =0. 000) had a higher risk than those with 5-HTR1 A (-1019) G allele ( OR = 3. 589,95% CI 2. 113-6. 096, P = 0. 000) or GNβ3 825T allele ( OR = 0. 638,95% CI 0.395-1. 031 ,P =0. 042) only for post-stroke depression. Conclusion The 5-HTR1A C( - 1019)G and GNβ3 C825T polymorphisms are predisposing genes of post-stroke depression. Our data also suggest a significant interaction between the 5-HTR1A ( - 1019)G allele and GNβ3 825T allele in post-stroke depression.

Negative feedback regulation of Wnt signaling by Gbetagamma-mediated reduction of Dishevelled

Wnt signaling is known to be important for diverse embryonic and post-natal cellular events and be regulated by the proteins Dishevelled and Axin. Although Dishevelled is activated by Wnt and involved in signal transduction, it is not clear how Dishevelled-mediated signaling is turned off. We report that guanine nucleotide binding protein beta 2 (Gnb2; Gbeta2) bound to Axin and Gbeta2 inhibited Wnt mediated reporter activity. The inhibition involved reduction of the level of Dishevelled, and the Gbeta2gamma2 mediated reduction of Dishevelled was countered by increased expression of Axin. Consistent with these effects in HEK293T cells, injection of Gbeta2gamma2 into Xenopus embryos inhibited the formation of secondary axes induced either by XWnt8 or Dishevelled, but not by beta-catenin. The DEP domain of Dishevelled is necessary for both interaction with Gbeta2gamma2 and subsequent degradation of Dishevelled via the lysosomal pathway. Signaling induced by Gbeta2gamma2 is required because a mutant of Gbeta2, Gbeta2 (W332A) with lower signaling activity, had reduced ability to downregulate the level of Dishevelled. Activation of Wnt signaling by either of two methods, increased Frizzled signaling or transient transfection of Wnt, also led to increased degradation of Dishevelled and the induced Dishevelled loss is dependent on Gbeta1 and Gbeta2. Other studies with agents that interfere with PLC action and calcium signaling suggested that loss of Dishevelled is mediated through the following pathway: Wnt/Frizzled-->Gbetagamma-->PLC-->Ca+2/PKC signaling. Together the evidence suggests a novel negative feedback mechanism in which Gbeta2gamma2 inhibits Wnt signaling by degradation of Dishevelled.

Inhibition of gamma ray-induced apoptosis by stimulatory heterotrimeric GTP binding protein involves Bcl-xL down-regulation in SH-SY5Y human neuroblastoma cells

Heterotrimeric GTP-binding proteins (G proteins) transduce extracellular signals into intracellular signals by activating effector molecules including adenylate cyclases that catalyze cAMP formation, and thus regulate various cellular responses such as metabolism, proliferation, and apoptosis. cAMP signaling pathways have been reported to protect cells from ionizing radiation-induced apoptosis, but however, the protective mechanism is not clear. Therefore, this study aimed to investigate the signaling molecules and the mechanism mediating the anti-apoptotic action of cAMP signaling system in radiation-induced apoptosis. Stable expression of a constitutively active mutant of G alpha s (G alpha sQL) protected gamma ray-induced apoptosis which was assessed by analysis of the cleavages of PARP, caspase-9, and caspase-3 and cytochrome C release in SH-SY5Y human neuroblastoma cells. G alpha sQL repressed the gamma ray-induced down-regulation of Bcl-xL protein, but transfection of Bcl-xL siRNA increased the gamma ray-induced apoptosis and abolished the anti-apoptotic effect of G alpha sQL. G alpha sQL decreased the degradation rate of Bcl-xL protein, and it also restrained the decrease in Bcl-xL mRNA by increasing the stability following ionizing irradiation. Furthermore, prostaglandin E2 that activates G alpha s was found to protect gamma ray-induced apoptosis, and the protective effect was abolished by treatment with prostanoid receptor antagonist specific to EP2/4R subtype. Moreover, specific agonists for adenosine A1 receptor that inhibits cAMP signaling pathway augmented gamma ray-induced apoptosis. From this study, it is concluded that Galphas-cAMP signaling system can protect SH-SY5Y cells from gamma ray-induced apoptosis partly by restraining down-regulation of Bcl-xL expression, suggesting that radiation-induced apoptosis can be modulated by GPCR ligands to improve the efficiency of radiation therapy.

THE PRELIMINARY STUDY ON THE CHANGES IN THE EXPRESSION OF G PROTEINS ? SUBUNIT mRNA IN THYROID TUMOR / 解放军医学杂志

To investigate the changes in the expression of G proteins ? subunit mRNA in non functioning thyroid adenoma (NFTA) and thyroid papillary cancer (TPC). Eleven thyroid specimens were obtained during surgery, 6 of which from patients with NFTA and 5 from patients with TPC. The expression levels of stimulating and inhibiting G protein ? subunit mRNAs were determined by reverse transcription polymerase chain reaction (RT PCR). The expression levels of Gsa mRNA in TPCs were significantly higher than those in normal thyroids and NFTAs( P