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Role of cyclic nucleotide-dependent actin cytoskeletal dynamics:Ca(2+)](i) and force suppression in forskolin-pretreated porcine coronary arteries.
Hocking KM, Baudenbacher FJ, Putumbaka G, Venkatraman S, Cheung-Flynn J, Brophy CM, Komalavilas P
(2013) PLoS One 8: e60986
MeSH Terms: Actin Cytoskeleton, Actin Depolymerizing Factors, Actins, Animals, Biomechanical Phenomena, Calcium, Cell Adhesion Molecules, Colforsin, Coronary Vessels, HSP20 Heat-Shock Proteins, Histamine, Intracellular Space, Microfilament Proteins, Muscle Contraction, Myosin Light Chains, Nucleotides, Cyclic, Paxillin, Phosphoproteins, Phosphorylation, Sus scrofa
Show Abstract · Added March 9, 2015
Initiation of force generation during vascular smooth muscle contraction involves a rise in intracellular calcium ([Ca(2+)]i) and phosphorylation of myosin light chains (MLC). However, reversal of these two processes alone does not account for the force inhibition that occurs during relaxation or inhibition of contraction, implicating that other mechanisms, such as actin cytoskeletal rearrangement, play a role in the suppression of force. In this study, we hypothesize that forskolin-induced force suppression is dependent upon changes in actin cytoskeletal dynamics. To focus on the actin cytoskeletal changes, a physiological model was developed in which forskolin treatment of intact porcine coronary arteries (PCA) prior to treatment with a contractile agonist resulted in complete suppression of force. Pretreatment of PCA with forskolin suppressed histamine-induced force generation but did not abolish [Ca(2+)]i rise or MLC phosphorylation. Additionally, forskolin pretreatment reduced filamentous actin in histamine-treated tissues, and prevented histamine-induced changes in the phosphorylation of the actin-regulatory proteins HSP20, VASP, cofilin, and paxillin. Taken together, these results suggest that forskolin-induced complete force suppression is dependent upon the actin cytoskeletal regulation initiated by the phosphorylation changes of the actin regulatory proteins and not on the MLC dephosphorylation. This model of complete force suppression can be employed to further elucidate the mechanisms responsible for smooth muscle tone, and may offer cues to pathological situations, such as hypertension and vasospasm.
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20 MeSH Terms
An essential role for modulation of hyperpolarization-activated current in the development of binaural temporal precision.
Khurana S, Liu Z, Lewis AS, Rosa K, Chetkovich D, Golding NL
(2012) J Neurosci 32: 2814-23
MeSH Terms: Age Factors, Analysis of Variance, Androstadienes, Animals, Biophysical Phenomena, Bucladesine, Colforsin, Cyclic Nucleotide-Gated Cation Channels, Electric Stimulation, Enzyme Inhibitors, Female, Gene Expression Regulation, Developmental, Gerbillinae, Imidazoles, In Vitro Techniques, Ion Channel Gating, Male, Neurons, Olivary Nucleus, Patch-Clamp Techniques, Pyridines, Pyrimidines, Wortmannin
Show Abstract · Added April 2, 2019
In sensory circuits of the brain, developmental changes in the expression and modulation of voltage-gated ion channels are a common occurrence, but such changes are often difficult to assign to clear functional roles. We have explored this issue in the binaural neurons of the medial superior olive (MSO), whose temporal precision in detecting the coincidence of binaural inputs dictates the resolution of azimuthal sound localization. We show that in MSO principal neurons of gerbils during the first week of hearing, a hyperpolarization-activated current (I(h)) progressively undergoes a 13-fold increase in maximal conductance, a >10-fold acceleration of kinetics, and, most surprisingly, a 30 mV depolarizing shift in the voltage dependence of activation. This period is associated with an upregulation of the hyperpolarization-activated and cyclic nucleotide-gated (HCN) channel subunits HCN1, HCN2, and HCN4 in the MSO, but only HCN1 and HCN4 were expressed strongly in principal neurons. I(h) recorded in nucleated patches from electrophysiologically mature MSO neurons (>P18) exhibited kinetics and an activation range nearly identical to the I(h) found in whole-cell recordings before hearing onset. These results indicate that the developmental changes in I(h) in MSO neurons can be explained predominantly by modulation from diffusible intracellular factors, and not changes in channel subunit composition. The exceptionally large modulatory changes in I(h), together with refinements in synaptic properties transform the coding strategy from one of summation and integration to the submillisecond coincidence detection known to be required for transmission of sound localization cues.
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Acute stimulation of white adipocyte respiration by PKA-induced lipolysis.
Yehuda-Shnaidman E, Buehrer B, Pi J, Kumar N, Collins S
(2010) Diabetes 59: 2474-83
MeSH Terms: Adipocytes, White, Aerobiosis, Anaerobiosis, Animals, Bucladesine, Colforsin, Cyclic AMP, Humans, Ion Channels, Isoproterenol, Isoquinolines, Male, Mice, Mice, Knockout, Mitochondrial Proteins, Oxygen Consumption, Protein Kinase Inhibitors, RNA, Small Interfering, Reverse Transcriptase Polymerase Chain Reaction, Sulfonamides, Uncoupling Protein 2
Show Abstract · Added July 23, 2020
OBJECTIVE - We examined the effect of β-adrenergic receptor (βAR) activation and cAMP-elevating agents on respiration and mitochondrial uncoupling in human adipocytes and probed the underlying molecular mechanisms.
RESEARCH DESIGN AND METHODS - Oxygen consumption rate (OCR, aerobic respiration) and extracellular acidification rate (ECAR, anaerobic respiration) were examined in response to isoproterenol (ISO), forskolin (FSK), and dibutyryl-cAMP (DB), coupled with measurements of mitochondrial depolarization, lipolysis, kinase activities, and gene targeting or knock-down approaches.
RESULTS - ISO, FSK, or DB rapidly increased oxidative and glycolytic respiration together with mitochondrial depolarization in human and mouse white adipocytes. The increase in OCR was oligomycin-insensitive and contingent on cAMP-dependent protein kinase A (PKA)-induced lipolysis. This increased respiration and the uncoupling were blocked by inhibiting the mitochondrial permeability transition pore (PTP) and its regulator, BAX. Interestingly, compared with lean individuals, adipocytes from obese subjects exhibited reduced OCR and uncoupling capacity in response to ISO.
CONCLUSIONS - Lipolysis stimulated by βAR activation or other maneuvers that increase cAMP levels in white adipocytes acutely induces mitochondrial uncoupling and cellular energetics, which are amplified in the absence of scavenging BSA. The increase in OCR is dependent on PKA-induced lipolysis and is mediated by the PTP and BAX. Because this effect is reduced with obesity, further exploration of this uncoupling mechanism will be needed to determine its cause and consequences.
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Axonal neuregulin 1 type III activates NF-kappaB in Schwann cells during myelin formation.
Limpert AS, Carter BD
(2010) J Biol Chem 285: 16614-22
MeSH Terms: Animals, Axons, COS Cells, Chlorocebus aethiops, Colforsin, Gene Deletion, Mice, Models, Biological, Myelin Sheath, NF-kappa B, Neuregulin-1, Protein Isoforms, Protein Structure, Tertiary, Pyrimidines, Pyrroles, Rats, Rats, Sprague-Dawley, Schwann Cells, Signal Transduction
Show Abstract · Added March 5, 2014
The formation of myelin requires a series of complex signaling events initiated by the axon to surrounding glial cells, which ultimately respond by tightly wrapping the axon with layers of specialized plasma membrane thereby allowing for saltatory conduction. Activation of the transcription factor NF-kappaB in Schwann cells has been suggested to be critical for these cells to differentiate into a myelinating phenotype; however, the mechanisms by which it is activated have yet to be elucidated. Here, we demonstrate that axonal membranes are sufficient to promote NF-kappaB activation in cultured Schwann cells and identify neuregulin 1 (NRG1), specifically the membrane-bound type III isoform, as the signal responsible for activating this transcription factor. Surprisingly, neither membrane-bound type I nor the soluble NRG1 EGF domain could activate NF-kappaB, indicating that type III induces a qualitatively unique signal. The transcriptional activity of NF-kappaB was significantly enhanced by treatment with forskolin, indicating these two signals converge for maximal activation. Both ErbB2 and -3 receptors were required for transducing the NRG1 signal, because gene deletion of ErbB3 in Schwann cells or treatment with the ErbB2 selective inhibitor, PKI-166, prevented the stimulation of NF-kappaB by axonal membranes. Finally, PKI-166 blocked the activation of the transcription factor in myelinating neuron/Schwann cell co-cultures and in vivo, in developing sciatic nerves. Taken together, these data establish NRG1 type III as the activator of NF-kappaB during myelin formation.
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19 MeSH Terms
GSK3beta mediates renal response to vasopressin by modulating adenylate cyclase activity.
Rao R, Patel S, Hao C, Woodgett J, Harris R
(2010) J Am Soc Nephrol 21: 428-37
MeSH Terms: Adenylyl Cyclases, Animals, Antidiuretic Agents, Aquaporin 2, Cells, Cultured, Colforsin, Cyclic AMP, Deamino Arginine Vasopressin, Female, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Kidney Concentrating Ability, Kidney Tubules, Collecting, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, RNA, Messenger, Water Deprivation, Water-Electrolyte Balance
Show Abstract · Added August 19, 2013
Glycogen synthase kinase 3beta (GSK3beta), a serine/threonine protein kinase, is a key target of drug discovery in several diseases, including diabetes and Alzheimer disease. Because lithium, a potent inhibitor of GSK3beta, causes nephrogenic diabetes insipidus, GSK3beta may play a crucial role in regulating water homeostasis. We developed renal collecting duct-specific GSK3beta knockout mice to determine whether deletion of GSK3beta affects arginine vasopressin-dependent renal water reabsorption. Although only mildly polyuric under normal conditions, knockout mice exhibited an impaired urinary concentrating ability in response to water deprivation or treatment with a vasopressin analogue. The knockout mice had reduced levels of mRNA, protein, and membrane localization of the vasopressin-responsive water channel aquaporin 2 compared with wild-type mice. The knockout mice also expressed lower levels of pS256-AQP2, a phosphorylated form crucial for membrane trafficking. Levels of cAMP, a major regulator of aquaporin 2 expression and trafficking, were also lower in the knockout mice. Both GSK3beta gene deletion and pharmacologic inhibition of GSK3beta reduced adenylate cyclase activity. In summary, GSK3beta inactivation or deletion reduces aquaporin 2 expression by modulating adenylate cyclase activity and cAMP generation, thereby impairing responses to vasopressin in the renal collecting duct.
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20 MeSH Terms
Altered hippocampal long-term synaptic plasticity in mice deficient in the PGE2 EP2 receptor.
Yang H, Zhang J, Breyer RM, Chen C
(2009) J Neurochem 108: 295-304
MeSH Terms: Alprostadil, Animals, Animals, Newborn, Colforsin, Cyclooxygenase Inhibitors, Dinoprostone, Electric Stimulation, Enzyme Inhibitors, Excitatory Postsynaptic Potentials, Hippocampus, In Vitro Techniques, Long-Term Potentiation, Maze Learning, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Neurons, Nitrobenzenes, Patch-Clamp Techniques, Physical Phenomena, Reaction Time, Receptors, Prostaglandin E, Receptors, Prostaglandin E, EP2 Subtype, Signal Transduction, Sulfonamides, Synapses, Time Factors
Show Abstract · Added December 21, 2013
Our laboratory demonstrated previously that PGE2-induced modulation of hippocampal synaptic transmission is via a pre-synaptic PGE2 EP2 receptor. However, little is known about whether the EP2 receptor is involved in hippocampal long-term synaptic plasticity and cognitive function. Here we show that long-term potentiation at the hippocampal perforant path synapses was impaired in mice deficient in the EP2 (KO), while membrane excitability and passive properties in granule neurons were normal. Importantly, escape latency in the water maze in EP2 KO was longer than that in age-matched EP2 wild-type littermates (WT). We also observed that long-term potentiation was potentiated in EP2 WT animals that received lipopolysaccharide (LPS, i.p.), but not in EP2 KO. Bath application of PGE2 or butaprost, an EP2 receptor agonist, increased synaptic transmission and decreased paired-pulses ratio in EP2 WT mice, but failed to induce the changes in EP2 KO mice. Meanwhile, synaptic transmission was elevated by application of forskolin, an adenylyl cyclase activator, both in EP2 KO and WT animals. In addition, the PGE2-enhanced synaptic transmission was significantly attenuated by application of PKA, IP3 or MAPK inhibitors in EP2 WT animals. Our results show that hippocampal long-term synaptic plasticity is impaired in mice deficient in the EP2, suggesting that PGE2-EP2 signaling is important for hippocampal long-term synaptic plasticity and cognitive function.
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28 MeSH Terms
Interferon-stimulated gene ISG12b1 inhibits adipogenic differentiation and mitochondrial biogenesis in 3T3-L1 cells.
Li B, Shin J, Lee K
(2009) Endocrinology 150: 1217-24
MeSH Terms: 3T3-L1 Cells, Adenoviridae, Adipogenesis, Adipose Tissue, Amino Acid Sequence, Animals, Cell Differentiation, Colforsin, Down-Regulation, Gene Expression Regulation, Interferons, Membrane Proteins, Mice, Mice, Obese, Mitochondria, Molecular Sequence Data, Proteins, Transduction, Genetic
Show Abstract · Added March 3, 2014
Microarray analysis was performed to find a new group of genes or pathways that might be important in adipocyte development and metabolism. Among them, a mouse interferon-stimulated gene 12b1 (ISG12b1) is expressed at a 400-fold higher level in adipocytes compared with stromal-vascular cells. It is predominantly expressed in adipose tissue among other tissues we tested. Developmentally, ISG12b1 mRNA expression was initially inhibited followed by a dramatic induction during both in vivo and in vitro adipogenic differentiation. Adenovirus-mediated overexpression of ISG12b1 inhibited adipogenic differentiation in 3T3-L1 cells as shown by decreased lipid staining with Oil-Red-O and reduction in adipogenic marker proteins including peroxisome proliferator-activated receptor-gamma (PPARgamma), and CCAAT/enhancer-binding protein-alpha (C/EBPalpha). Our bioinformatics analysis for the predicted localization of ISG12b1 protein suggested the mitochondrial localization, which was confirmed by the colocalization of hemagglutinin-tagged ISG12b1 protein with mitochondrial marker MitoTracker. In addition, ISG12b1 protein was exclusively detected in protein extract from the fractionated mitochondria by Western blot analysis. Furthermore, overexpression of ISG12b1 in adipocytes reduced mitochondrial DNA content and gene expression of mitochondrial transcription factor A (mtTFA), nuclear respiratory factor 1 (NRF1), and cytochrome oxidase II, suggesting an inhibitory role of ISG12b1 in mitochondrial biogenesis and function. Activation of mitochondrial biogenesis and function by treatment with PPARgamma and PPARalpha agonists in 3T3-L1 cells and cold exposure in mice induced mitochondrial transcription factors and reduced ISG12 expression. These data demonstrated that mitochondrial-localized ISG12b1 protein inhibits adipocyte differentiation and mitochondrial biogenesis and function, implying the important role of mitochondrial function in adipocyte development and associated diseases.
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18 MeSH Terms
Liver X receptor alpha is a transcriptional repressor of the uncoupling protein 1 gene and the brown fat phenotype.
Wang H, Zhang Y, Yehuda-Shnaidman E, Medvedev AV, Kumar N, Daniel KW, Robidoux J, Czech MP, Mangelsdorf DJ, Collins S
(2008) Mol Cell Biol 28: 2187-200
MeSH Terms: Adaptor Proteins, Signal Transducing, Adipocytes, Brown, Adrenergic beta-Agonists, Animals, Body Temperature, Cell Differentiation, Cells, Cultured, Colforsin, DNA-Binding Proteins, Enhancer Elements, Genetic, Ion Channels, Liver X Receptors, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria, Mitochondrial Proteins, Nuclear Proteins, Nuclear Receptor Interacting Protein 1, Orphan Nuclear Receptors, Oxygen Consumption, PPAR gamma, RNA, Small Interfering, Receptors, Cytoplasmic and Nuclear, Signal Transduction, Transcription, Genetic, Uncoupling Protein 1
Show Abstract · Added July 22, 2020
The adipocyte integrates crucial information about metabolic needs in order to balance energy intake, storage, and expenditure. Whereas white adipose tissue stores energy, brown adipose tissue is a major site of energy dissipation through adaptive thermogenesis mediated by uncoupling protein 1 (UCP1) in mammals. In both white and brown adipose tissue, nuclear receptors and their coregulators, such as peroxisome proliferator-activated receptor gamma (PPARgamma) and PPARgamma coactivator 1alpha (PGC-1alpha), play key roles in regulating their development and metabolic functions. Here we show the unexpected role of liver X receptor alpha (LXRalpha) as a direct transcriptional inhibitor of beta-adrenergic receptor-mediated, cyclic AMP-dependent Ucp1 gene expression through its binding to the critical enhancer region of the Ucp1 promoter. The mechanism of inhibition involves the differential recruitment of the corepressor RIP140 to an LXRalpha binding site that overlaps with the PPARgamma/PGC-1alpha response element, resulting in the dismissal of PPARgamma. The ability of LXRalpha to dampen energy expenditure in this way provides another mechanism for maintaining a balance between energy storage and utilization.
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Developmental, hormonal, and nutritional regulation of porcine adipose triglyceride lipase (ATGL).
Deiuliis JA, Shin J, Bae D, Azain MJ, Barb R, Lee K
(2008) Lipids 43: 215-25
MeSH Terms: Adipocytes, Adipogenesis, Adipose Tissue, White, Amino Acid Sequence, Animals, Base Sequence, Caloric Restriction, Cell Differentiation, Cells, Cultured, Colforsin, Cyclic AMP-Dependent Protein Kinases, Insulin, Lipase, Lipolysis, Molecular Sequence Data, Muscle, Striated, Sequence Alignment, Swine
Show Abstract · Added March 3, 2014
Adipose triglyceride lipase (ATGL) is a newly identified lipase. We report for the first time the porcine ATGL sequence and characterize ATGL gene and protein expression in vitro and in vivo. Adult pig tissue expresses ATGL at high levels in the white adipose and muscle tissue relative to other tested tissues. We show that within the white adipose tissue ATGL is expressed at higher levels in the adipocyte than in the stromal-vascular fraction. Additionally, ATGL expression increases dramatically in the subcutaneous adipose during adipose development and maturation, as well as during in vitro adipogenesis. Peroxisome proliferator-activated receptor gamma transcript levels increased concomitant with ATGL gene expression, suggesting a possible role in the regulation of ATGL by adipogenic regulators. In vitro treatment of differentiated primary pig preadipocytes with insulin and forskolin decreased ATGL gene expression in a dose-dependent manner, suggesting ATGL transcript levels are hormone sensitive. In vivo experimentation showed that calorie-restriction in gilts resulted in increased ATGL mRNA and protein levels in subcutaneous and peri-renal fat tissues. Our data demonstrate that ATGL expression reacts to hormonal stimuli and plays a role in catecholamine-induced lipolysis in porcine adipose tissue.
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18 MeSH Terms
The small heat shock-related protein, HSP20, is a cAMP-dependent protein kinase substrate that is involved in airway smooth muscle relaxation.
Komalavilas P, Penn RB, Flynn CR, Thresher J, Lopes LB, Furnish EJ, Guo M, Pallero MA, Murphy-Ullrich JE, Brophy CM
(2008) Am J Physiol Lung Cell Mol Physiol 294: L69-78
MeSH Terms: Animals, Cattle, Colforsin, Cyclic AMP-Dependent Protein Kinases, HSP20 Heat-Shock Proteins, Isoproterenol, Kinetics, Muscle Relaxation, Muscle, Smooth, Phosphopeptides, Respiratory Physiological Phenomena, Serotonin
Show Abstract · Added December 10, 2013
Activation of the cAMP/cAMP-dependent PKA pathway leads to relaxation of airway smooth muscle (ASM). The purpose of this study was to examine the role of the small heat shock-related protein HSP20 in mediating PKA-dependent ASM relaxation. Human ASM cells were engineered to constitutively express a green fluorescent protein-PKA inhibitory fusion protein (PKI-GFP) or GFP alone. Activation of the cAMP-dependent signaling pathways by isoproterenol (ISO) or forskolin led to increases in the phosphorylation of HSP20 in GFP but not PKI-GFP cells. Forskolin treatment in GFP but not PKI-GFP cells led to a loss of central actin stress fibers and decreases in the number of focal adhesion complexes. This loss of stress fibers was associated with dephosphorylation of the actin-depolymerizing protein cofilin in GFP but not PKI-GFP cells. To confirm that phosphorylated HSP20 plays a role in PKA-induced ASM relaxation, intact strips of bovine ASM were precontracted with serotonin followed by ISO. Activation of the PKA pathway led to relaxation of bovine ASM, which was associated with phosphorylation of HSP20 and dephosphorylation of cofilin. Finally, treatment with phosphopeptide mimetics of HSP20 possessing a protein transduction domain partially relaxed precontracted bovine ASM strips. In summary, ISO-induced phosphorylation of HSP20 or synthetic phosphopeptide analogs of HSP20 decreases phosphorylation of cofilin and disrupts actin in ASM, suggesting that one possible mechanism by which HSP20 mediates ASM relaxation is via regulation of actin filament dynamics.
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12 MeSH Terms