Faculty Research

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    Glycine Potentiates AMPA Receptor Function through Metabotropic Activation of GIuN2A-Containing NMDA Receptors
    (2016) Li, Li-Jun; Hu, Rong; Lujan, Brendan J.; Chen, Juan; Zhang, Jian-Jian; Nakano, Yasuko; Cui, Tian-Yuan; Liao, Ming-Xia; Chen, Jin-Cao; Man, Heng-Ye; Feng, Hua; Wan, Qi
    NMDA receptors are Ca2+.-permeable ion channels. The activation of NMDA receptors requires agonist glutamate and co-agonist glycine. Recent evidence indicates that NMDA receptor also has metabotropic function. Here we report that in cultured mouse hippocampal neurons, glycine increases AMPA receptor -mediated currents independent of the channel activity of NMDA receptors and the activation of glycine receptors. The potentiation of AMPA receptor function by glycine is antagonized by the inhibition of ERK1/2. In the hippocampal neurons and in the HEK293 cells transfected with different combinations of NMDA receptors, glycine preferentially acts on GIuN2A-containing NMDA receptors (GIuN2ARs), but not GIuN2B-containing NMDA receptors (GIuN2BRs), to enhance ERK1/2 phosphorylation independent of the channel activity of GIuN2ARs. Without requiring the channel activity of GIuN2ARs, glycine increases AMPA receptor -mediated currents through GIuN2ARs. Thus, these results reveal a metabotropic function of GIuN2ARs in mediating glycine-induced potentiation of AMPA receptor function via ERK1/2 activation.
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    SpermBase: A Database for Sperm-Borne RNA Contents
    (2016) Schuster, Andrew; Tang, Chong; Xie, Yeming; Ortogero, Nicole; Yuan, Shuiqiao; Yan, Wei
    Since their discovery approximately three decades ago, sperm-borne RNAs, both large/small and coding/noncoding, have been reported in multiple organisms, and some have been implicated in spermatogenesis, early development, and epigenetic inheritance. Despite these advances, isolation, quantification, and annotation of sperm-borne RNAs remain nontrivial. The yields and subspecies of sperm-borne RNAs isolated from sperm can vary drastically depending on the methods used, and no cross-species analyses of sperm RNA contents have ever been conducted using a standardized sperm RNA isolation protocol. To address these issues, we developed a simple RNA isolation method that is applicable to sperm of various species, thus allowing for reliable interspecies comparisons. Based on RNASeq analyses, we established SpermBase (www.spermbase.org), a database dedicated to sperm-borne RNA profiling of multiple species. Currently, SpermBase contains large and small RNA expression data for mouse, rat, rabbit, and human total sperm and sperm heads. By analyzing large and small RNAs for conserved features, we found that many sperm-borne RNA species were conserved across all four species analyzed, and among the conserved small RNAs, sperm-borne tRNA-derived small noncoding RNAs and miRNAs can target a large number of genes known to be critical for early development.
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    Glycine triggers a non-ionotropic activity of GluN2A-containing NMDA receptors to confer neuroprotection
    (2016) Hu, Rong; Chen, Juan; Lujan, Brendan J.; Lei, Ruixue; Zhang, Mi; Wang, Zefen; Liao, Mingxia; Li, Zhiqiang; Wan, Yu; Liu, Fang; Feng, Hua; Wan, Qi
    Ionotropic activation of NMDA receptors (NMDARs) requires agonist glutamate and co-agonist glycine. Here we show that glycine enhances the activation of cell survival-promoting kinase Akt in cultured cortical neurons in which both the channel activity of NMDARs and the glycine receptors are pre-inhibited. The effect of glycine is reduced by shRNA-mediated knockdown of GluN2A subunit-containing NMDARs (GluN2ARs), suggesting that a non-ionotropic activity of GluN2ARs mediates glycine-induced Akt activation. In support of this finding, glycine enhances Akt activation in HEK293 cells over-expressing GluN2ARs. The effect of glycine on Akt activation is sensitive to the antagonist of glycine-GluN1 binding site. As a functional consequence, glycine protects against excitotoxicity-induced neuronal death through the non-ionotropic activity of GluN2ARs and the neuroprotective effect is attenuated by Akt inhibition. Thus, this study reveals an unexpected role of glycine in eliciting a non-ionotropic activity of GluN2ARs to confer neuroprotection via Akt activation.
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    Genome Sequence Variability Predicts Drug Precautions and Withdrawals from the Market
    (2016) Lee, Kye H.; Baik, Su Y.; Lee, Soo Y.; Park, Chanjae H.; Park, Paul J.; Kim, Ju H.
    Despite substantial premarket efforts, a significant portion of approved drugs has been withdrawn from the market for safety reasons. The deleterious impact of nonsynonymous substitutions predicted by the SIFT algorithm on structure and function of drug-related proteins was evaluated for 2504 personal genomes. Both withdrawn (n = 154) and precautionary (Beers criteria (n = 90), and US FDA pharmacogenomic biomarkers (n = 96)) drugs showed significantly lower genomic deleteriousness scores (P < 0.001) compared to others (n = 752). Furthermore, the rates of drug withdrawals and precautions correlated significantly with the deleteriousness scores of the drugs (P < 0.01) this trend was confirmed for all drugs included in the withdrawal and precaution lists by the United Nations, European Medicines Agency, DrugBank, Beers criteria, and US FDA. Our findings suggest that the person-to-person genome sequence variability is a strong independent predictor of drug withdrawals and precautions. We propose novel measures of drug safety based on personal genome sequence analysis.
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    KCa3.1 Transgene Induction in Murine Intestinal Epithelium Causes Duodenal Chyme Accumulation and Impairs Duodenal Contractility
    (2019) Valero, Marta S.; Ramon-Gimenez, Mariano; Lozano-Gerona, Javier; Delgado-Wicke, Pablo; Calmarza, Pilar; Olivan-Viguera, Aida; Lopez, Victor S.; Garcia-Otin, Angel-Luis; Valero, Salvador; Pueyo, Esther; Hamilton, Kirk L.; Miura, Hiroto; Kohler, Ralf
    The epithelial intermediate-conductance calcium/calmodulin-regulated KCa3.1 channel is considered to be a regulator of intestine function by controlling chloride secretion and water/salt balance. Yet, little is known about the functional importance of KCa3.1 in the intestinal epithelium in vivo. Our objective was to determine the impact of epithelial-specific inducible overexpression of a KCa3.1 transgene (KCa3.1+) and of inducible suppression (KCa3.1-) on intestinal homeostasis and function in mice. KCa3.1 overexpression in the duodenal epithelium of doxycycline (DOX)-treated KCa3.1+ mice was 40-fold above the control levels. Overexpression caused an inflated duodenum and doubling of the chyme content. Histology showed conserved architecture of crypts, villi, and smooth muscle. Unaltered proliferating cell nuclear antigen (PCNA) immune reactivity and reduced amounts of terminal deoxynucleotide transferase mediated X-dUTP nick end labeling (TUNEL)-positive apoptotic cells in villi indicated lower epithelial turnover. Myography showed a reduction in the frequency of spontaneous propulsive muscle contractions with no change in amplitude. The amount of stool in the colon was increased and the frequency of colonic contractions was reduced in KCa3.1+ animals. Senicapoc treatment prevented the phenotype. Suppression of KCa3.1 in DOX-treated KCa3.1- mice caused no overt intestinal phenotype. In conclusion, inducible KCa3.1 overexpression alters intestinal functions by increasing the chyme content and reducing spontaneous contractions and epithelial apoptosis. Induction of epithelial KCa3.1 can play a mechanistic role in the process of adaptation of the intestine.