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Teresa K. Aman Bruce A. Maki Thomas J. Ruffino Eileen M. Kasperek Gabriela K. Popescu 《The Journal of biological chemistry》2014,289(27):18805-18817
Protein kinase A (PKA) enhances synaptic plasticity in the central nervous system by increasing NMDA receptor current amplitude and Ca2+ flux in an isoform-dependent yet poorly understood manner. PKA phosphorylates multiple residues on GluN1, GluN2A, and GluN2B subunits in vivo, but the functional significance of this multiplicity is unknown. We examined gating and permeation properties of recombinant NMDA receptor isoforms and of receptors with altered C-terminal domain (CTDs) prior to and after pharmacological inhibition of PKA. We found that PKA inhibition decreased GluN1/GluN2B but not GluN1/GluN2A gating; this effect was due to slower rates for receptor activation and resensitization and was mediated exclusively by the GluN2B CTD. In contrast, PKA inhibition reduced NMDA receptor-relative Ca2+ permeability (PCa/PNa) regardless of the GluN2 isoform and required the GluN1 CTD; this effect was due primarily to decreased unitary Ca2+ conductance, because neither Na+ conductance nor Ca2+-dependent block was altered substantially. Finally, we show that both the gating and permeation effects can be reproduced by changing the phosphorylation state of a single residue: GluN2B Ser-1166 and GluN1 Ser-897, respectively. We conclude that PKA effects on NMDA receptor gating and Ca2+ permeability rely on distinct phosphorylation sites located on the CTD of GluN2B and GluN1 subunits. This separate control of NMDA receptor properties by PKA may account for the specific effects of PKA on plasticity during synaptic development and may lead to drugs targeted to alter NMDA receptor gating or Ca2+ permeability. 相似文献
3.
George V. Sharonov Eduard V. Bocharov Peter M. Kolosov Maria V. Astapova Alexander S. Arseniev Alexey V. Feofanov 《The Journal of biological chemistry》2014,289(21):14955-14964
The EphA2 receptor tyrosine kinase plays a central role in the regulation of cell adhesion and guidance in many human tissues. The activation of EphA2 occurs after proper dimerization/oligomerization in the plasma membrane, which occurs with the participation of extracellular and cytoplasmic domains. Our study revealed that the isolated transmembrane domain (TMD) of EphA2 embedded into the lipid bicelle dimerized via the heptad repeat motif L535X3G539X2A542X3V546X2L549 rather than through the alternative glycine zipper motif A536X3G540X3G544 (typical for TMD dimerization in many proteins). To evaluate the significance of TMD interactions for full-length EphA2, we substituted key residues in the heptad repeat motif (HR variant: G539I, A542I, G553I) or in the glycine zipper motif (GZ variant: G540I, G544I) and expressed YFP-tagged EphA2 (WT, HR, and GZ variants) in HEK293T cells. Confocal microscopy revealed a similar distribution of all EphA2-YFP variants in cells. The expression of EphA2-YFP variants and their kinase activity (phosphorylation of Tyr588 and/or Tyr594) and ephrin-A3 binding were analyzed with flow cytometry on a single cell basis. Activation of any EphA2 variant is found to occur even without ephrin stimulation when the EphA2 content in cells is sufficiently high. Ephrin-A3 binding is not affected in mutant variants. Mutations in the TMD have a significant effect on EphA2 activity. Both ligand-dependent and ligand-independent activities are enhanced for the HR variant and reduced for the GZ variant compared with the WT. These findings allow us to suggest TMD dimerization switching between the heptad repeat and glycine zipper motifs, corresponding to inactive and active receptor states, respectively, as a mechanism underlying EphA2 signal transduction. 相似文献
4.
表面活性剂的疏水性及电性对肌酸激酶的活力及复性能力的影响 总被引:4,自引:0,他引:4
测定了烷基硫酸钠(CnH_(2n+1)SO_4Na;记为CnS;n=8,10,12)和溴化十烷基三甲铵C_(10)H_(21)(CH_3)Br;记为C_(10)NM_3)对肌酸激酶(CreatineKinase;记为C.K.)的活力,以及在它们中变性后复活能力的影响。CnS对C.K.的变性效率随n的增加而增加,变性效率的对数和n之间有线性关系;CnS水C.K.的变性能力远大于C_(10)NM_3;C.K.被C_(10)NM_3变性以后,其复性能力(稀释时恢复活力的程度远大于C.K.被CnS变性后活力的恢复能力。这种差别主要是由于C_(10)NM_3带正电,而CnS带负电引起的。 相似文献
5.
A rat complementary DNA (cDNA) for the RI beta isoform of type I cyclic adenosine monophosphate (cAMP)-dependent protein kinase regulatory subunit was cloned and sequenced and was found to contain the entire protein coding and 3'-untranslated regions, with a single (ATTAAA) poly-adenylation site. The largest open reading frame was preceded by a short out-of-phase open reading frame, which is not seen in the corresponding mouse RI beta cDNA due to a single base substitution. The rat RI beta cDNA clone was 2,374 bases long and detected a rat mRNA of approximately 2.8 kilobases. Rat RI beta mRNA was abundant in adult rat brain and testis but was undetectable in other rat tissues. The rat RI beta cDNA also detected RI beta mRNA in mouse brain, but not mouse testis, from 10-week-old BALB/c or 10- and 6-week-old Swiss Webster mice. Thus, despite a 96% nucleotide identity in the coding region of RI beta in rat vs. mouse, there are at least two differences in these closely related species. First, there is a short open reading frame, which precedes the coding region in the rat but not the mouse. Second, unlike the mouse testis, the rat testis contains abundant levels of RI beta mRNA. 相似文献
6.
7.
NAD激酶在光合作用等植物生理过程中起重要作用。NAD激酶的激活依赖于钙离子和钙调素(CalmOdulin,CaM).从植物中分离得到的一种新的CaM结合蛋白CaMBP-10(BP-10)明显抑制NAD激酶的激活活性,抑制作用可被CaM所克服.动力学研究表明,抑制效应是BP-10与CaM之间特异性相互作用的结果。实验证实BP-10对NAD激酶活性起着重要调节作用. 相似文献
8.
Induction of a Nerve Growth Factor-Sensitive Kinase that Phosphorylates the DNA-Binding Domain of the Orphan Nuclear Receptor NGFI-B 总被引:2,自引:0,他引:2
Yoko Hirata Michael Whalin David D. Ginty Jun Xing Michael E. Greenberg †Jeffrey Milbrandt Gordon Guroff 《Journal of neurochemistry》1995,65(4):1780-1788
Abstract: Nerve growth factor (NGF) induces the synthesis and the phosphorylation of the orphan nuclear receptor NGFI-B in PC12 cells. Previous work has shown that phosphorylation, by protein kinase A, of a specific serine in the DNA-binding domain inhibits its binding to the NGFI-B response element. Also, cytoplasmic extracts from PC12 cells phosphorylate this serine, and phosphorylation is greater in extracts from cells treated with NGF. The present work describes the induction, identification, and partial purification of a kinase (termed NGFI-B kinase I) from PC12 cell extracts that catalyzes this phosphorylation. Phosphorylation of the DNA-binding domain with this purified preparation inhibits its binding to the NGFI-B response element. The kinase is rapidly activated by treatment of the cells with NGF, and the activation lasts for at least several hours. It also is activated by fibroblast growth factor and epidermal growth factor (EGF), but the activation by EGF is quite transient. The kinase requires Mg2+ but will use Mn2+ . The molecular mass of the kinase is 95–100 kDa, and it is different from protein kinase A, Fos kinase, or pp90 rsk . Comparison with a partially purified preparation of cyclic AMP response element-binding protein kinase, however, indicates that the two are either very similar or identical. 相似文献
9.
Conclusion Membrane association is essential for GRK function and because of this the GRKs have evolved complex regulatory mechanisms
for associating with the membrane. Although the GRKs are highly homologous, each kinase utilizes a distinct mechanism for
associating with the membrane, which makes it unique within the family. Initially, the carboxyl terminus of the GRKs was identified
as the “membrane association domain” but recent evidence suggests that the amino terminus may also play a critical role in
localizing the kinases to the membrane (Murga et al., 1996; Pitcher et al, 1996). It is within these two domains that the
GRKs are most variable at the amino acid level. The GRKS exhibit an absolute requirement for phospholipids not only for association
with the membrane but also for activity. There are differences in preference and binding sites for the phospholipids within
the GRK family, which may reflect differential targeting of the GRKs to G protein-coupled receptors situated in different
lipid environments. There are hundreds of G protein-coupled receptors and only six known GRKs. All the GRKs appear to phosphorylate
the same receptor substrates in vitro (Sterne-Marr & Benovic, 1995; Premont et al., 1995). Receptor specificity, in a cellular 相似文献
10.
Avihu Boneh 《Journal of cellular biochemistry》1995,59(1):27-32
Protein kinase C (PKC) is a ubiquitous enzyme family implicated in the regulation of a large number of short- and long-term intracellular processes. It is hypothesized that modulation of PKC activity may represent, at least in part, a functional link between mutations (genotype) that lead to the pathological accumulation of naturally occurring compounds that affect PKC activity and perturbation of PKC-mediated substrate phosphorylation and cellular function in the corresponding diseases (phenotype). This model provides a unifying putative mechanism by which the phenotypic expression of some inborn errors of metabolism may be explained. Recent studies in a cell-free system of human skin fibroblasts support the hypothesis that alteration of PKC activity may represent the functional link between accumulation of sphingolipids and fatty acyl-CoA esters, and perturbation of cell function in sphingolipidoses and fatty acid oxidation defects, respectively. Further studies will elucidate the effects of these alterations on PKC-mediated short- and long-term cellular functions in these diseases, as well as the possible role of PKC in the pathogensis of other diseases. © 1995 Wiley-Liss, Inc. 相似文献