Biomedical subjects

Taeho Kim

Publications and source records attributed to Taeho Kim.

5 recordsLinked to original sources

PubMed2006

Force-induced insulin dimer dissociation: a molecular dynamics study.

Understanding the forces and dynamics of insulin dissociation is critical for devising formulations for the treatment of insulin-dependent diabetes. In earlier work, we applied AFM-based force spectroscopy to covalently tethered and oriented insulin monomers to assess the effect of molecular orientation on insulin-insulin binding forces. We report here on steered molecular dynamics simulations of the insulin dissociation force spectroscopy experiment. Consistent with our experiments, our simulation results suggest that insulin dimer dissociation occurs near the limit of extensibility of the B-chain. We have also found that the forced dissociation of the insulin dimer is a rate-dependent process, involving significant conformational changes to the monomer(s). The insulin dimer dissociation pathway also depends on the relative strength of the inter-monomer interactions across the antiparallel beta-sheet interface and the intra-monomer interactions of residues A1 and A30 with the insulin B-chain. Our simulation results strongly support the design of bioactive insulin analogues that involves altering hydrogen bonding and hydrophobic interactions across the beta-sheet dimer interface.

Dimerization↗

PubMed2006

A nitric oxide signaling pathway controls CREB-mediated gene expression in neurons.

Prevailing views of neurotrophin action hold that the transcription factor CREB is constitutively bound to target genes with transcriptional activation occurring via CREB phosphorylation. However, we report that within several CRE-containing genes, CREB is not constitutively bound. Upon exposure of neurons to brain-derived neurotrophic factor (BDNF), CREB becomes rapidly bound to DNA coincident with phosphorylation at its transcriptional regulatory site, Ser133. This inducible CREB-DNA binding is independent of CREB Ser133 phosphorylation and is not affected by inhibition of the ERK or PI3K signaling pathways. Instead, BDNF regulates CREB binding by initiating a nitric oxide-dependent signaling pathway that leads to S-nitrosylation of nuclear proteins that associate with CREB target genes. Pharmacological manipulation of neurons in vitro and analysis of mice lacking neuronal nitric oxide synthase (nNOS) suggest that NO mediates BDNF and activity-dependent expression of CREB target genes. Thus, in conjunction with CREB phosphorylation, the NO pathway controls CREB-DNA binding and CRE-mediated gene expression.

Animals↗

PubMed2005

Nitric oxide-cGMP-protein kinase G signaling pathway induces anoxic preconditioning through activation of ATP-sensitive K+ channels in rat hearts.

Nitric oxide (NO) plays an important role in anoxic preconditioning to protect the heart against ischemia-reperfusion injuries. The present work was performed to study better the NO-cGMP-protein kinase G (PKG) signaling pathway in the activation of both sarcolemmal and mitochondrial ATP-sensitive K+ (KATP) channels during anoxic preconditioning (APC) and final influence on reducing anoxia-reperfusion (A/R)-induced cardiac damage in rat hearts. The upstream regulating elements controlling NO-cGMP-PKG signal-induced KATP channel opening that leads to cardioprotection were investigated. The involvement of both inducible and endothelial NO synthases (iNOS and eNOS) in the progression of this signaling pathway was followed. Final cellular outcomes of ischemia-induced injury after different preconditioning in the form of lactate dehydrogenase release, DNA strand breaks, and malondialdehyde formation as indexes of cell injury and lipid peroxidation, respectively, were investigated. The lactate dehydrogenase and malondialdehyde values decreased in the groups that underwent preconditioning periods with specific mitochondrial KATP channels opener diazoxide (100 microM), nonspecific mitochondrial KATP channels opener pinacidil (50 microM), S-nitroso-N-acetylpenicillamine (SNAP, 300 microM), or beta-phenyl-1,N2-etheno-8-bromoguanosine-3',5'-cyclicmonophosphorothioate, Sp-isomer (10 microM) before the A/R period. Preconditioning with SNAP significantly reduced the DNA damage. The effect was blocked by glibenclamide (50 microM), 5-hydroxydecanoate (100 microM), NG-nitro-L-arginine methyl ester (200 microM), and beta-phenyl-1,N2-etheno-8-bromoguanosine-3',5'-cyclic monophosphorothioate, Rp-isomer (1 microM). The results suggest iNOS, rather than eNOS, as the major contributing NO synthase during APC treatment. Moreover, the PKG shows priority over NO as the upstream regulator of NO-cGMP-PKG signal-induced KATP channel opening that leads to cardioprotection during APC treatment.

Animals↗

PubMed2004

Evaluation of a proposed mechanism of ligand-gated ion channel activation in the GABAA and glycine receptors.

Ligand-gated ion channels (LGICs) mediate rapid chemical neurotransmission in the mammalian brain. This gene superfamily includes the nicotinic acetylcholine (nAChR), GABA(A), 5-hydroxytryptamine type 3, and glycine receptors. Upon agonist binding these receptors undergo a rapid allosteric transition from the closed to open state. The molecular mechanism of coupling between agonist binding and channel gating remains poorly understood, in part due to the lack of a high-resolution structure of the entire receptor. Miyazawa, Fujiyoshi, and Unwin published a 4A resolution structure of the nAChR, and proposed that a single residue--valine 44 in Loop 2 of the extracellular domain--functions as a critical determinant of a "pin-into-socket" mechanism for receptor activation in nAChR. Here we examined whether this proposed "pin-into-socket" mechanism also contributes to channel activation in the GABA(A) and glycine receptors. We mutated residues corresponding to nAChR valine 44 in the GABA(A) (alpha(1) histidine 56 and beta(2) valine 53) and glycine (alpha(1) threonine 54) receptors. The results obtained in this study do not support a simple "pin-into-socket" mechanism of activation for the activation of GABA(A) and glycine receptors. This conclusion is consistent with other recent reports in which mutations of residues distributed throughout several loops of nAChR, GABA(A) and glycine receptors had large effects on gating behavior.

Amino Acid Sequence↗

PubMed2002

Monocyte cell adhesion induced by a human aminoacyl-tRNA synthetase-associated factor, p43: identification of the related adhesion molecules and signal pathways.

An aminoacyl-tRNA synthetase-associated factor, p43, was recently shown to be secreted to induce a proinflammatory response. Because a proinflammatory response involves the cell-cell adhesion between endothelial and immune cells, we first examined the mechanism of p43-induced cell-cell adhesion of myelomonocytic leukemia cells. Intercellular adhesion molecule-1 (ICAM-1) was up-regulated by p43 and mediated p43-induced cell-cell adhesion via the interaction with LFA-1 or Mac-1. We also investigated p43-stimulated signaling pathways involved in the homotypic THP-1 cell adhesion. Because the specific inhibitors for PI3-K (phosphatidylinositol 3-kinase), ERK (extracellular signal-regulating kinase), and p38 MAPK (mitogen-activated protein kinase) blocked p43-stimulated ICAM-1 expression and homotypic THP-1 cell adhesion, these kinases were responsible for p43-induced cell-cell adhesion. p43-Dependent activation of ERK was inhibited by PI3-K inhibitors, and the activation of p38 MAPK was not. Thus, the results of this work suggest that p43 should induce cell-cell adhesion via the PI3-K/ERK- and p38 MAPK-dependent up-regulation of ICAM-1.

Amino Acyl-tRNA Synthetases↗