Background G protein signaling pathways are key neuromodulatory mechanisms for behaviors and neurological functions that affect the impact of ethanol (EtOH) on locomotion, arousal, and synaptic plasticity. Here, we report a novel role for the Drosophila G protein–coupled receptor kinase 2 (GPRK2) as a member of the GRK4/5/6 subfamily in modulating EtOH‐induced behaviors. Methods We studied the requirement of Drosophila Gprk2 for naïve sensitivity to EtOH sedation and ability of the fly to develop rapid tolerance after a single exposure to EtOH, using the loss of righting reflex (LORR) and fly group activity monitor (FlyGrAM) assays. Results Loss‐of‐function Gprk2 mutants demonstrate an increase in alcohol‐induced hyperactivity, reduced sensitivity to the sedative effects of EtOH, and diminished rapid tolerance after a single intoxicating exposure. The requirement for Gprk2 in EtOH sedation and rapid tolerance maps to ellipsoid body neurons within the Drosophila brain, suggesting that wild‐type Gprk2 is required for modulation of locomotion and alertness. However, even though Gprk2 loss of function leads to decreased and fragmented sleep, this change in the sleep state does not depend on Gprk2 expression in the ellipsoid body. Conclusion Our work on GPRK2 has established a role for this GRK4/5/6 subfamily member in EtOH sensitivity and rapid tolerance.
Hyperoxia is cytotoxic and depresses many cellular metabolic functions including protein synthesis. Translational control is exerted primarily during initiation by two mechanisms: 1) through inhibition of translation initiation complex formation via sequestration of the cap-binding protein, eukaryotic initiation factor (eIF) 4E, with inhibitory 4E-binding proteins (4E-BP); and 2) by prevention of formation and eIF2B activity by phosphorylated eIF2α. In this report, exposure of human lung fibroblasts to 95% O 2 decreased the incorporation of thymidine into DNA at 6 h and the incorporation of leucine into protein beginning at 12 h. The reductions in DNA and protein synthesis were accompanied by increased phosphorylation of eIF4E protein and reduced phosphorylation of 4E-BP1. At 24 h, hyperoxia shifted 4E-BP1 phosphorylation to lesserphosphorylated isoforms, increased eIF4E expression, and increased the association of eIF4E with 4E-BP1. Although hyperoxia did not change eIF2α expression, it increased its phosphorylation at Ser51, but not until 48 h. In addition, the activation of eIF2α was not accompanied by the formation of stress granules. These findings suggest that hyperoxia diminishes protein synthesis by increasing eIF4E phosphorylation and enhancing the affinity of 4E-BP1 for eIF4E. Keywordseukaryotic translation initiation factors; protein synthesis; lung; stress granules Exposure of the developing lung to high concentrations of inspired oxygen is known to inhibit lung growth, both acutely and chronically (7,26). Cell culture and whole animal studies indicate that hyperoxia inhibits not only DNA synthesis but also protein synthesis (2,7,15,23). In adult rats breathing 95% O 2 , the fractional rate of protein synthesis and the rate of protein synthesis per ribosome are depressed by 30% within 6 h (7). Similarly, whole lung slices from rats exposed to hyperoxia for 24 and 48 h show 25% reductions in protein synthetic capacity of both total protein and newly synthesized proteins (15). At the cellular level, Jornot and colleagues (12) revealed that exposure to 95% O 2 inhibited the incorporation of leucine into protein, delayed the ribosomal transit time, and marginally increased the polysome content of cultured endothelial cells. Yet despite the near universality of the inhibitory effect of hyperoxia In mammalian cells, translation is principally regulated by a family of eukaryotic initiation factors (eIF) that control the assembly of the ribosome on the mRNA. The efficiency of ribosome/mRNA binding is governed by the availability of the 5′ m 7 -GpppX (where X is any nucleotide) mRNA cap binding protein, eIF4E, which, together with eIF4G and eIF4A, comprises the heterotrimeric eIF4F initiation complex (reviewed in Refs. 29 and 34). The eIF4F complex, along with eIF3, facilitates the assembly of the 43S ribosomal subunit on the 5′ end of the mRNA. The low abundance of eIF4E relative to the other 4F components renders it rate limiting for eIF4F formation. The level of free eIF4E is regulated by a group o...
Drosophila’s white gene encodes an ATP-binding cassette G-subfamily (ABCG) half-transporter. White is closely related to mammalian ABCG family members that function in cholesterol efflux. Mutants of white have several behavioral phenotypes that are independent of visual defects. This study characterizes a novel defect of white mutants in the acquisition of olfactory memory using the aversive olfactory conditioning paradigm. The w1118 mutants learned slower than wildtype controls, yet with additional training, they reached wildtype levels of performance. The w1118 learning phenotype is also found in the wapricot and wcoral alleles, is dominant, and is rescued by genomic white and mini-white transgenes. Reducing dietary cholesterol strongly impaired olfactory learning for wildtype controls, while w1118 mutants were resistant to this deficit. The w1118 mutants displayed higher levels of cholesterol and cholesterol esters than wildtype under this low-cholesterol diet. Increasing levels of serotonin, dopamine, or both in the white mutants significantly improved w1118 learning. However, serotonin levels were not lower in the heads of the w1118 mutants than in wildtype controls. There were also no significant differences found in synapse numbers within the w1118 brain. We propose that the w1118 learning defect may be due to inefficient biogenic amine signaling brought about by altered cholesterol homeostasis.
This paper attempts to inform and educate readers to some of the more recent changes in infrared material pricing and availability along with the impact of optical manufacturing trends and the means by which optical designers, manufacturers and product end-users are using to avoid or eliminate the pitfalls these changes may create.
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