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Publication Record


Chronic Intermittent Ethanol and Acute Stress Similarly Modulate BNST CRF Neuron Activity via Noradrenergic Signaling.
Snyder AE, Salimando GJ, Winder DG, Silberman Y
(2019) Alcohol Clin Exp Res 43: 1695-1701
MeSH Terms: Adrenergic Neurons, Animals, Corticotropin-Releasing Hormone, Ethanol, Excitatory Amino Acid Antagonists, Gene Knock-In Techniques, Glutamic Acid, Kynurenic Acid, Male, Membrane Potentials, Mice, Norepinephrine, Picrotoxin, Propranolol, Restraint, Physical, Septal Nuclei, Substance Withdrawal Syndrome
Show Abstract · Added March 30, 2020
BACKGROUND - Relapse is a critical barrier to effective long-term treatment of alcoholism, and stress is often cited as a key trigger to relapse. Numerous studies suggest that stress-induced reinstatement to drug-seeking behaviors is mediated by norepinephrine (NE) and corticotropin-releasing factor (CRF) signaling interactions in the bed nucleus of the stria terminalis (BNST), a brain region critical to many behavioral and physiologic responses to stressors. Here, we sought to directly examine the effects of NE on BNST CRF neuron activity and determine whether these effects may be modulated by chronic intermittent EtOH (CIE) exposure or a single restraint stress.
METHODS - Adult male CRF-tomato reporter mice were treatment-naïve, or either exposed to CIE for 2 weeks or to a single 1-hour restraint stress. Effects of application of exogenous NE on BNST CRF neuron activity were assessed via whole-cell patch-clamp electrophysiological techniques.
RESULTS - We found that NE depolarized BNST CRF neurons in naïve mice in a β-adrenergic receptor (AR)-dependent mechanism. CRF neurons from CIE- or stress-exposed mice had significantly elevated basal resting membrane potential compared to naïve mice. Furthermore, CIE and stress individually disrupted the ability of NE to depolarize CRF neurons, suggesting that both stress and CIE utilize β-AR signaling to modulate BNST CRF neurons. Neither stress nor CIE altered the ability of exogenous NE to inhibit evoked glutamatergic transmission onto BNST CRF neurons as shown in naïve mice, a mechanism previously shown to be α-AR-dependent.
CONCLUSIONS - Altogether, these findings suggest that stress and CIE interact with β-AR signaling to modulate BNST CRF neuron activity, potentially disrupting the α/β-AR balance of BNST CRF neuronal excitability. Restoration of α/β-AR balance may lead to novel therapies for the alleviation of many stress-related disorders.
© 2019 by the Research Society on Alcoholism.
0 Communities
1 Members
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17 MeSH Terms
Electrophysiologic and molecular mechanisms of a frameshift NPPA mutation linked with familial atrial fibrillation.
Menon A, Hong L, Savio-Galimberti E, Sridhar A, Youn SW, Zhang M, Kor K, Blair M, Kupershmidt S, Darbar D
(2019) J Mol Cell Cardiol 132: 24-35
MeSH Terms: Action Potentials, Animals, Atrial Fibrillation, Atrial Natriuretic Factor, Electrophysiological Phenomena, Frameshift Mutation, Heart Atria, Humans, Membrane Potentials, Mice, Mice, Transgenic, Myocytes, Cardiac, NAV1.5 Voltage-Gated Sodium Channel
Show Abstract · Added June 14, 2019
A frameshift (fs) mutation in the natriuretic peptide precursor A (NPPA) gene, encoding a mutant atrial natriuretic peptide (Mut-ANP), has been linked with familial atrial fibrillation (AF) but the underlying mechanisms by which the mutation causes AF remain unclear. We engineered 2 transgenic (TG) mouse lines expressing the wild-type (WT)-NPPA gene (H-WT-NPPA) and the human fs-Mut-NPPA gene (H-fsMut-NPPA) to test the hypothesis that mice overexpressing the human NPPA mutation are more susceptible to AF and elucidate the underlying electrophysiologic and molecular mechanisms. Transthoracic echocardiography and surface electrocardiography (ECG) were performed in H-fsMut-NPPA, H-WT-NPPA, and Non-TG mice. Invasive electrophysiology, immunohistochemistry, Western blotting and patch clamping of membrane potentials were performed. To examine the role of the Mut-ANP in ion channel remodeling, we measured plasma cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) levels and protein kinase A (PKA) activity in the 3 groups of mice. In H-fsMut-NPPA mice mean arterial pressure (MAP) was reduced when compared to H-WT-NPPA and Non-TG mice. Furthermore, injection of synthetic fs-Mut-ANP lowered the MAP in H-WT-NPPA and Non-TG mice while synthetic WT-ANP had no effect on MAP in the 3 groups of mice. ECG characterization revealed significantly prolonged QRS duration in H-fsMut-NPPA mice when compared to the other two groups. Trans-Esophageal (TE) atrial pacing of H-fsMut-NPPA mice showed increased AF burden and AF episodes when compared with H-WT-NPPA or Non-TG mice. The cardiac Na (NaV1.5) and Ca (CaV1.2/CaV1.3) channel expression and currents (I, I) and action potential durations (APD/APD/APD) were significantly reduced in H-fsMut-NPPA mice while the rectifier K channel current (I) was markedly increased when compared to the other 2 groups of mice. In addition, plasma cGMP levels were only increased in H-fsMut-NPPA mice with a corresponding reduction in plasma cAMP levels and PKA activity. In summary, we showed that mice overexpressing an AF-linked NPPA mutation are more prone to develop AF and this risk is mediated in part by remodeling of the cardiac Na, Ca and K channels creating an electrophysiologic substrate for reentrant AF.
Copyright © 2019 Elsevier Ltd. All rights reserved.
1 Communities
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13 MeSH Terms
Late onset obesity in mice with targeted deletion of potassium inward rectifier Kir7.1 from cells expressing the melanocortin-4 receptor.
Anderson EJP, Ghamari-Langroudi M, Cakir I, Litt MJ, Chen V, Reggiardo RE, Millhauser GL, Cone RD
(2019) J Neuroendocrinol 31: e12670
MeSH Terms: Animals, Feeding Behavior, Female, Hypothalamus, Male, Membrane Potentials, Mice, Inbred C57BL, Mice, Knockout, Neurons, Obesity, Potassium Channels, Inwardly Rectifying, Receptor, Melanocortin, Type 4
Show Abstract · Added January 8, 2019
Energy stores in fat tissue are determined in part by the activity of hypothalamic neurones expressing the melanocortin-4 receptor (MC4R). Even a partial reduction in MC4R expression levels in mice, rats or humans produces hyperphagia and morbid obesity. Thus, it is of great interest to understand the molecular basis of neuromodulation by the MC4R. The MC4R is a G protein-coupled receptor that signals efficiently through Gα , and this signalling pathway is essential for normal MC4R function in vivo. However, previous data from hypothalamic slice preparations indicated that activation of the MC4R depolarised neurones via G protein-independent regulation of the ion channel Kir7.1. In the present study, we show that deletion of Kcnj13 (ie, the gene encoding Kir7.1) specifically from MC4R neurones produced resistance to melanocortin peptide-induced depolarisation of MC4R paraventricular nucleus neurones in brain slices, resistance to the sustained anorexic effect of exogenously administered melanocortin peptides, late onset obesity, increased linear growth and glucose intolerance. Some MC4R-mediated phenotypes appeared intact, including Agouti-related peptide-induced stimulation of food intake and MC4R-mediated induction of peptide YY release from intestinal L cells. Thus, a subset of the consequences of MC4R signalling in vivo appears to be dependent on expression of the Kir7.1 channel in MC4R cells.
© 2018 British Society for Neuroendocrinology.
1 Communities
0 Members
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12 MeSH Terms
Simultaneous Real-Time Measurement of the β-Cell Membrane Potential and Ca Influx to Assess the Role of Potassium Channels on β-Cell Function.
Vierra NC, Dickerson MT, Philipson LH, Jacobson DA
(2018) Methods Mol Biol 1684: 73-84
MeSH Terms: Animals, Calcium, Cells, Cultured, Humans, Insulin-Secreting Cells, Membrane Potentials, Mice, Patch-Clamp Techniques, Potassium Channels
Show Abstract · Added November 13, 2017
Stimulus-secretion coupling in pancreatic β-cells requires Ca influx through voltage-dependent Ca channels, whose activity is controlled by the plasma membrane potential (V ). Here, we present a method of measuring fluctuations in the β-cell V and Ca influx simultaneously, which provides valuable information about the ionic signaling mechanisms that underlie insulin secretion. This chapter describes the use of perforated patch clamp electrophysiology on cells loaded with a fluorescent intracellular Ca indicator, which permits the stable recording conditions needed to monitor the V and Ca influx in β-cells. Moreover, this chapter describes the protocols necessary for the preparation of mouse and human islet cells for the simultaneous recording of V and Ca as well as determining the specific islet cell type assessed in each experiment.
0 Communities
1 Members
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9 MeSH Terms
Osteopontin activates the diabetes-associated potassium channel TALK-1 in pancreatic β-cells.
Dickerson MT, Vierra NC, Milian SC, Dadi PK, Jacobson DA
(2017) PLoS One 12: e0175069
MeSH Terms: Aged, Animals, Calcium Signaling, Diabetes Mellitus, Type 2, Female, Glucose, HEK293 Cells, Humans, Insulin, Insulin Secretion, Insulin-Secreting Cells, Membrane Potentials, Mice, Knockout, Osteopontin, Potassium, Potassium Channels, Tandem Pore Domain
Show Abstract · Added November 13, 2017
Glucose-stimulated insulin secretion (GSIS) relies on β-cell Ca2+ influx, which is modulated by the two-pore-domain K+ (K2P) channel, TALK-1. A gain-of-function polymorphism in KCNK16, the gene encoding TALK-1, increases risk for developing type-2 diabetes. While TALK-1 serves an important role in modulating GSIS, the regulatory mechanism(s) that control β-cell TALK-1 channels are unknown. Therefore, we employed a membrane-specific yeast two-hybrid (MYTH) assay to identify TALK-1-interacting proteins in human islets, which will assist in determining signaling modalities that modulate TALK-1 function. Twenty-one proteins from a human islet cDNA library interacted with TALK-1. Some of these interactions increased TALK-1 activity, including intracellular osteopontin (iOPN). Intracellular OPN is highly expressed in β-cells and is upregulated under pre-diabetic conditions to help maintain normal β-cell function; however, the functional role of iOPN in β-cells is poorly understood. We found that iOPN colocalized with TALK-1 in pancreatic sections and coimmunoprecipitated with human islet TALK-1 channels. As human β-cells express two K+ channel-forming variants of TALK-1, regulation of these TALK-1 variants by iOPN was assessed. At physiological voltages iOPN activated TALK-1 transcript variant 3 channels but not TALK-1 transcript variant 2 channels. Activation of TALK-1 channels by iOPN also hyperpolarized resting membrane potential (Vm) in HEK293 cells and in primary mouse β-cells. Intracellular OPN was also knocked down in β-cells to test its effect on β-cell TALK-1 channel activity. Reducing β-cell iOPN significantly decreased TALK-1 K+ currents and increased glucose-stimulated Ca2+ influx. Importantly, iOPN did not affect the function of other K2P channels or alter Ca2+ influx into TALK-1 deficient β-cells. These results reveal the first protein interactions with the TALK-1 channel and found that an interaction with iOPN increased β-cell TALK-1 K+ currents. The TALK-1/iOPN complex caused Vm hyperpolarization and reduced β-cell glucose-stimulated Ca2+ influx, which is predicted to inhibit GSIS.
0 Communities
1 Members
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16 MeSH Terms
An interplay between the serotonin transporter (SERT) and 5-HT receptors controls stimulus-secretion coupling in sympathoadrenal chromaffin cells.
Brindley RL, Bauer MB, Blakely RD, Currie KPM
(2016) Neuropharmacology 110: 438-448
MeSH Terms: Adrenal Glands, Animals, Calcium, Calcium Channels, N-Type, Cations, Divalent, Cells, Cultured, Chromaffin Cells, Exocytosis, Male, Membrane Potentials, Mice, Inbred C57BL, Mice, Knockout, Potassium Channels, Voltage-Gated, Receptors, Serotonin, Serotonin, Serotonin Agents, Serotonin Plasma Membrane Transport Proteins
Show Abstract · Added August 22, 2016
Adrenal chromaffin cells (ACCs), the neuroendocrine arm of the sympathetic nervous system, secrete catecholamines to mediate the physiological response to stress. Although ACCs do not synthesize 5-HT, they express the serotonin transporter (SERT). Genetic variations in SERT are linked to several CNS disorders but the role(s) of SERT/5-HT in ACCs has remained unclear. Adrenal glands from wild-type mice contained 5-HT at ≈ 750 fold lower abundance than adrenaline, and in SERT(-/-) mice this was reduced by ≈80% with no change in catecholamines. Carbon fibre amperometry showed that SERT modulated the ability of 5-HT1A receptors to inhibit exocytosis. 5-HT reduced the number of amperometric spikes (vesicular fusion events) evoked by KCl in SERT(-/-) cells and wild-type cells treated with escitalopram, a SERT antagonist. The 5-HT1A receptor antagonist WAY100635 blocked the inhibition by 5-HT which was mimicked by the 5-HT1A agonist 8-OH-DPAT but not the 5-HT1B agonist CP93129. There was no effect on voltage-gated Ca(2+) channels, K(+) channels, or intracellular [Ca(2+)] handling, showing the 5-HT receptors recruit an atypical inhibitory mechanism. Spike charge and kinetics were not altered by 5-HT receptors but were reduced in SERT(-/-) cells compared to wild-type cells. Our data reveal a novel role for SERT and suggest that adrenal chromaffin cells might be a previously unrecognized hub for serotonergic control of the sympathetic stress response.
Copyright © 2016 Elsevier Ltd. All rights reserved.
0 Communities
1 Members
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17 MeSH Terms
Comparison of γ-Aminobutyric Acid, Type A (GABAA), Receptor αβγ and αβδ Expression Using Flow Cytometry and Electrophysiology: EVIDENCE FOR ALTERNATIVE SUBUNIT STOICHIOMETRIES AND ARRANGEMENTS.
Botzolakis EJ, Gurba KN, Lagrange AH, Feng HJ, Stanic AK, Hu N, Macdonald RL
(2016) J Biol Chem 291: 20440-61
MeSH Terms: Epilepsy, Flow Cytometry, Gene Expression Regulation, HEK293 Cells, Humans, Membrane Potentials, Protein Subunits, Receptors, GABA
Show Abstract · Added March 14, 2018
The subunit stoichiometry and arrangement of synaptic αβγ GABAA receptors are generally accepted as 2α:2β:1γ with a β-α-γ-β-α counterclockwise configuration, respectively. Whether extrasynaptic αβδ receptors adopt the analogous β-α-δ-β-α subunit configuration remains controversial. Using flow cytometry, we evaluated expression levels of human recombinant γ2 and δ subunits when co-transfected with α1 and/or β2 subunits in HEK293T cells. Nearly identical patterns of γ2 and δ subunit expression were observed as follows: both required co-transfection with α1 and β2 subunits for maximal expression; both were incorporated into receptors primarily at the expense of β2 subunits; and both yielded similar FRET profiles when probed for subunit adjacency, suggesting similar underlying subunit arrangements. However, because of a slower rate of δ subunit degradation, 10-fold less δ subunit cDNA was required to recapitulate γ2 subunit expression patterns and to eliminate the functional signature of α1β2 receptors. Interestingly, titrating γ2 or δ subunit cDNA levels progressively altered GABA-evoked currents, revealing more than one kinetic profile for both αβγ and αβδ receptors. This raised the possibility of alternative receptor isoforms, a hypothesis confirmed using concatameric constructs for αβγ receptors. Taken together, our results suggest a limited cohort of alternative subunit arrangements in addition to canonical β-α-γ/δ-β-α receptors, including β-α-γ/δ-α-α receptors at lower levels of γ2/δ expression and β-α-γ/δ-α-γ/δ receptors at higher levels of expression. These findings provide important insight into the role of GABAA receptor subunit under- or overexpression in disease states such as genetic epilepsies.
© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.
0 Communities
1 Members
0 Resources
8 MeSH Terms
ML418: The First Selective, Sub-Micromolar Pore Blocker of Kir7.1 Potassium Channels.
Swale DR, Kurata H, Kharade SV, Sheehan J, Raphemot R, Voigtritter KR, Figueroa EE, Meiler J, Blobaum AL, Lindsley CW, Hopkins CR, Denton JS
(2016) ACS Chem Neurosci 7: 1013-23
MeSH Terms: Animals, Dose-Response Relationship, Drug, HEK293 Cells, Humans, Membrane Potentials, Models, Molecular, Mutagenesis, Site-Directed, Mutation, Patch-Clamp Techniques, Potassium, Potassium Channel Blockers, Potassium Channels, Inwardly Rectifying, Structure-Activity Relationship, Time Factors, Transfection
Show Abstract · Added April 8, 2017
The inward rectifier potassium (Kir) channel Kir7.1 (KCNJ13) has recently emerged as a key regulator of melanocortin signaling in the brain, electrolyte homeostasis in the eye, and uterine muscle contractility during pregnancy. The pharmacological tools available for exploring the physiology and therapeutic potential of Kir7.1 have been limited to relatively weak and nonselective small-molecule inhibitors. Here, we report the discovery in a fluorescence-based high-throughput screen of a novel Kir7.1 channel inhibitor, VU714. Site-directed mutagenesis of pore-lining amino acid residues identified glutamate 149 and alanine 150 as essential determinants of VU714 activity. Lead optimization with medicinal chemistry generated ML418, which exhibits sub-micromolar activity (IC50 = 310 nM) and superior selectivity over other Kir channels (at least 17-fold selective over Kir1.1, Kir2.1, Kir2.2, Kir2.3, Kir3.1/3.2, and Kir4.1) except for Kir6.2/SUR1 (equally potent). Evaluation in the EuroFins Lead Profiling panel of 64 GPCRs, ion-channels, and transporters for off-target activity of ML418 revealed a relatively clean ancillary pharmacology. While ML418 exhibited low CLHEP in human microsomes which could be modulated with lipophilicity adjustments, it showed high CLHEP in rat microsomes regardless of lipophilicity. A subsequent in vivo PK study of ML418 by intraperitoneal (IP) administration (30 mg/kg dosage) revealed a suitable PK profile (Cmax = 0.20 μM and Tmax = 3 h) and favorable CNS distribution (mouse brain/plasma Kp of 10.9 to support in vivo studies. ML418, which represents the current state-of-the-art in Kir7.1 inhibitors, should be useful for exploring the physiology of Kir7.1 in vitro and in vivo.
1 Communities
2 Members
0 Resources
15 MeSH Terms
Hyperpolarization-independent maturation and refinement of GABA/glycinergic connections in the auditory brain stem.
Lee H, Bach E, Noh J, Delpire E, Kandler K
(2016) J Neurophysiol 115: 1170-82
MeSH Terms: Animals, GABAergic Neurons, Glycine, Membrane Potentials, Mice, Neurogenesis, Superior Olivary Complex, Symporters, Synapses, gamma-Aminobutyric Acid
Show Abstract · Added May 3, 2017
During development GABA and glycine synapses are initially excitatory before they gradually become inhibitory. This transition is due to a developmental increase in the activity of neuronal potassium-chloride cotransporter 2 (KCC2), which shifts the chloride equilibrium potential (ECl) to values more negative than the resting membrane potential. While the role of early GABA and glycine depolarizations in neuronal development has become increasingly clear, the role of the transition to hyperpolarization in synapse maturation and circuit refinement has remained an open question. Here we investigated this question by examining the maturation and developmental refinement of GABA/glycinergic and glutamatergic synapses in the lateral superior olive (LSO), a binaural auditory brain stem nucleus, in KCC2-knockdown mice, in which GABA and glycine remain depolarizing. We found that many key events in the development of synaptic inputs to the LSO, such as changes in neurotransmitter phenotype, strengthening and elimination of GABA/glycinergic connection, and maturation of glutamatergic synapses, occur undisturbed in KCC2-knockdown mice compared with wild-type mice. These results indicate that maturation of inhibitory and excitatory synapses in the LSO is independent of the GABA and glycine depolarization-to-hyperpolarization transition.
Copyright © 2016 the American Physiological Society.
0 Communities
1 Members
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10 MeSH Terms
VU0477573: Partial Negative Allosteric Modulator of the Subtype 5 Metabotropic Glutamate Receptor with In Vivo Efficacy.
Nickols HH, Yuh JP, Gregory KJ, Morrison RD, Bates BS, Stauffer SR, Emmitte KA, Bubser M, Peng W, Nedelcovych MT, Thompson A, Lv X, Xiang Z, Daniels JS, Niswender CM, Lindsley CW, Jones CK, Conn PJ
(2016) J Pharmacol Exp Ther 356: 123-36
MeSH Terms: Allosteric Regulation, Animals, Anti-Anxiety Agents, Astrocytes, Behavior, Animal, Brain, Dose-Response Relationship, Drug, Drug Discovery, GABA Agonists, HEK293 Cells, Humans, Inositol Phosphates, MAP Kinase Signaling System, Membrane Potentials, Mice, Mice, Inbred C57BL, Picolinic Acids, Pyridines, Radioligand Assay, Rats, Receptor, Metabotropic Glutamate 5, Synaptic Transmission
Show Abstract · Added February 18, 2016
Negative allosteric modulators (NAMs) of metabotropic glutamate receptor subtype 5 (mGlu5) have potential applications in the treatment of fragile X syndrome, levodopa-induced dyskinesia in Parkinson disease, Alzheimer disease, addiction, and anxiety; however, clinical and preclinical studies raise concerns that complete blockade of mGlu5 and inverse agonist activity of current mGlu5 NAMs contribute to adverse effects that limit the therapeutic use of these compounds. We report the discovery and characterization of a novel mGlu5 NAM, N,N-diethyl-5-((3-fluorophenyl)ethynyl)picolinamide (VU0477573) that binds to the same allosteric site as the prototypical mGlu5 NAM MPEP but displays weak negative cooperativity. Because of this weak cooperativity, VU0477573 acts as a "partial NAM" so that full occupancy of the MPEP site does not completely inhibit maximal effects of mGlu5 agonists on intracellular calcium mobilization, inositol phosphate (IP) accumulation, or inhibition of synaptic transmission at the hippocampal Schaffer collateral-CA1 synapse. Unlike previous mGlu5 NAMs, VU0477573 displays no inverse agonist activity assessed using measures of effects on basal [(3)H]inositol phosphate (IP) accumulation. VU0477573 acts as a full NAM when measuring effects on mGlu5-mediated extracellular signal-related kinases 1/2 phosphorylation, which may indicate functional bias. VU0477573 exhibits an excellent pharmacokinetic profile and good brain penetration in rodents and provides dose-dependent full mGlu5 occupancy in the central nervous system (CNS) with systemic administration. Interestingly, VU0477573 shows robust efficacy, comparable to the mGlu5 NAM MTEP, in models of anxiolytic activity at doses that provide full CNS occupancy of mGlu5 and demonstrate an excellent CNS occupancy-efficacy relationship. VU0477573 provides an exciting new tool to investigate the efficacy of partial NAMs in animal models.
Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.
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3 Members
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22 MeSH Terms