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Intrinsic islet heterogeneity and gap junction coupling determine spatiotemporal Ca²⁺ wave dynamics.
Benninger RK, Hutchens T, Head WS, McCaughey MJ, Zhang M, Le Marchand SJ, Satin LS, Piston DW
(2014) Biophys J 107: 2723-33
MeSH Terms: Animals, Calcium Signaling, Gap Junctions, Glucose, Islets of Langerhans, Male, Mice, Mice, Knockout, Models, Biological, Time Factors
Show Abstract · Added January 20, 2015
Insulin is released from the islets of Langerhans in discrete pulses that are linked to synchronized oscillations of intracellular free calcium ([Ca(2+)]i). Associated with each synchronized oscillation is a propagating calcium wave mediated by Connexin36 (Cx36) gap junctions. A computational islet model predicted that waves emerge due to heterogeneity in β-cell function throughout the islet. To test this, we applied defined patterns of glucose stimulation across the islet using a microfluidic device and measured how these perturbations affect calcium wave propagation. We further investigated how gap junction coupling regulates spatiotemporal [Ca(2+)]i dynamics in the face of heterogeneous glucose stimulation. Calcium waves were found to originate in regions of the islet having elevated excitability, and this heterogeneity is an intrinsic property of islet β-cells. The extent of [Ca(2+)]i elevation across the islet in the presence of heterogeneity is gap-junction dependent, which reveals a glucose dependence of gap junction coupling. To better describe these observations, we had to modify the computational islet model to consider the electrochemical gradient between neighboring β-cells. These results reveal how the spatiotemporal [Ca(2+)]i dynamics of the islet depend on β-cell heterogeneity and cell-cell coupling, and are important for understanding the regulation of coordinated insulin release across the islet.
Copyright © 2014 Biophysical Society. Published by Elsevier Inc. All rights reserved.
0 Communities
1 Members
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10 MeSH Terms
Focal energy deprivation underlies arrhythmia susceptibility in mice with calcium-sensitized myofilaments.
Huke S, Venkataraman R, Faggioni M, Bennuri S, Hwang HS, Baudenbacher F, Knollmann BC
(2013) Circ Res 112: 1334-44
MeSH Terms: Adenosine Triphosphate, Adenylate Kinase, Animals, Arrhythmias, Cardiac, Calcium, Cardiomyopathy, Hypertrophic, Cardiotonic Agents, Connexin 43, Disease Models, Animal, Disease Susceptibility, Electrocardiography, Energy Metabolism, Female, Gap Junctions, Heterocyclic Compounds, 4 or More Rings, Male, Mice, Mice, Inbred Strains, Mice, Transgenic, Myofibrils, Quinolines, Thiadiazines
Show Abstract · Added May 27, 2014
RATIONALE - The Ca(2+) sensitivity of the myofilaments is increased in hypertrophic cardiomyopathy and other heart diseases and may contribute to a higher risk for sudden cardiac death. Ca(2+) sensitization increases susceptibility to reentrant ventricular tachycardia in animal models, but the underlying mechanism is unknown.
OBJECTIVE - To investigate how myofilament Ca(2+) sensitization creates reentrant arrhythmia susceptibility.
METHODS AND RESULTS - Using hypertrophic cardiomyopathy mouse models (troponinT-I79N) and a Ca(2+) sensitizing drug (EMD57033), here we identify focal energy deprivation as a direct consequence of myofilament Ca(2+) sensitization. To detect ATP depletion and thus energy deprivation, we measured accumulation of dephosphorylated Connexin 43 (Cx43) isoform P0 and AMP kinase activation by Western blotting and immunostaining. No differences were detected between groups at baseline, but regional accumulation of Connexin 43 isoform P0 occurred within minutes in all Ca(2+)-sensitized hearts, in vivo after isoproterenol challenge and in isolated hearts after rapid pacing. Lucifer yellow dye spread demonstrated reduced gap junctional coupling in areas with Connexin 43 isoform P0 accumulation. Optical mapping revealed that selectively the transverse conduction velocity was slowed and anisotropy increased. Myofilament Ca(2+) desensitization with blebbistatin prevented focal energy deprivation, transverse conduction velocity slowing, and the reentrant ventricular arrhythmias.
CONCLUSIONS - Myofilament Ca(2+) sensitization rapidly leads to focal energy deprivation and reduced intercellular coupling during conditions that raise arrhythmia susceptibility. This is a novel proarrhythmic mechanism that can increase arrhythmia susceptibility in structurally normal hearts within minutes and may, therefore, contribute to sudden cardiac death in diseases with increased myofilament Ca(2+) sensitivity.
0 Communities
2 Members
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22 MeSH Terms
UNC-4 antagonizes Wnt signaling to regulate synaptic choice in the C. elegans motor circuit.
Schneider J, Skelton RL, Von Stetina SE, Middelkoop TC, van Oudenaarden A, Korswagen HC, Miller DM
(2012) Development 139: 2234-45
MeSH Terms: Animals, Biomarkers, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Gap Junctions, Genes, Helminth, Glycoproteins, Green Fluorescent Proteins, Homeodomain Proteins, Interneurons, Models, Anatomic, Motor Neurons, Movement, Nerve Net, Nuclear Proteins, Receptors, Wnt, Recombinant Fusion Proteins, Synapses, Transcription Factors, Wnt Proteins, Wnt Signaling Pathway
Show Abstract · Added February 3, 2014
Coordinated movement depends on the creation of synapses between specific neurons in the motor circuit. In C. elegans, this important decision is regulated by the UNC-4 homeodomain protein. unc-4 mutants are unable to execute backward locomotion because VA motor neurons are mis-wired with inputs normally reserved for their VB sisters. We have proposed that UNC-4 functions in VAs to block expression of VB genes. This model is substantiated by the finding that ectopic expression of the VB gene ceh-12 (encoding a homolog of the homeodomain protein HB9) in unc-4 mutants results in the mis-wiring of posterior VA motor neurons with VB-like connections. Here, we show that VA expression of CEH-12 depends on a nearby source of the Wnt protein EGL-20. Our results indicate that UNC-4 prevents VAs from responding to a local EGL-20 cue by disabling a canonical Wnt signaling cascade involving the Frizzled receptors MIG-1 and MOM-5. CEH-12 expression in VA motor neurons is also opposed by a separate pathway that includes the Wnt ligand LIN-44. This work has revealed a transcriptional mechanism for modulating the sensitivity of specific neurons to diffusible Wnt ligands and thereby defines distinct patterns of synaptic connectivity. The existence of comparable Wnt gradients in the vertebrate spinal cord could reflect similar roles for Wnt signaling in vertebrate motor circuit assembly.
0 Communities
3 Members
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21 MeSH Terms
Connexin-36 gap junctions regulate in vivo first- and second-phase insulin secretion dynamics and glucose tolerance in the conscious mouse.
Head WS, Orseth ML, Nunemaker CS, Satin LS, Piston DW, Benninger RK
(2012) Diabetes 61: 1700-7
MeSH Terms: Animals, Blood Glucose, Calcium Signaling, Cells, Cultured, Connexins, Gap Junctions, Glucose Tolerance Test, Insulin, Insulin Secretion, Islets of Langerhans, Male, Mice, Mice, Knockout, Pancreas
Show Abstract · Added December 5, 2013
Insulin is secreted from the islets of Langerhans in coordinated pulses. These pulses are thought to lead to plasma insulin oscillations, which are putatively more effective in lowering blood glucose than continuous levels of insulin. Gap-junction coupling of β-cells by connexin-36 coordinates intracellular free calcium oscillations and pulsatile insulin release in isolated islets, however a role in vivo has not been shown. We test whether loss of gap-junction coupling disrupts plasma insulin oscillations and whether this impacts glucose tolerance. We characterized the connexin-36 knockout (Cx36(-/-)) mouse phenotype and performed hyperglycemic clamps with rapid sampling of insulin in Cx36(-/-) and control mice. Our results show that Cx36(-/-) mice are glucose intolerant, despite normal plasma insulin levels and insulin sensitivity. However, Cx36(-/-) mice exhibit reduced insulin pulse amplitudes and a reduction in first-phase insulin secretion. These changes are similarly found in isolated Cx36(-/-) islets. We conclude that Cx36 gap junctions regulate the in vivo dynamics of insulin secretion, which in turn is important for glucose homeostasis. Coordinated pulsatility of individual islets enhances the first-phase elevation and second-phase pulses of insulin. Because these dynamics are disrupted in the early stages of type 2 diabetes, dysregulation of gap-junction coupling could be an important factor in the development of this disease.
4 Communities
1 Members
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14 MeSH Terms
Physiological and molecular characterization of connexin hemichannels in zebrafish retinal horizontal cells.
Sun Z, Risner ML, van Asselt JB, Zhang DQ, Kamermans M, McMahon DG
(2012) J Neurophysiol 107: 2624-32
MeSH Terms: Animals, Animals, Genetically Modified, Connexins, Electrical Synapses, Gap Junctions, Membrane Potentials, Retinal Horizontal Cells, Synaptic Transmission, Zebrafish, Zebrafish Proteins
Show Abstract · Added March 18, 2020
Connexin channels mediate electrical synaptic transmission when assembled as cell-to-cell pores at gap junctions and can mediate transmembrane currents when expressed in plasma membranes as hemichannels. They are widely expressed in the vertebrate retina where in electrical synapses they are critical for transmission of visual signals. While the roles of connexins in electrical synapses are well-studied, the function and roles of connexin hemichannels in the nervous system are less well understood. Genetic deletion in zebrafish of connexin (Cx) 55.5 alters horizontal cell feedback to cones, spectral responses, and visual behavior. Here, we have characterized the properties of hemichannel currents in zebrafish retinal horizontal cells and examined the roles of two connexin isoforms, Cx55.5 and Cx52.6, that are coexpressed in these cells. We report that zebrafish horizontal cells express hemichannel currents that conduct inward current at physiological negative potentials and Ca(2+) levels. Manipulation of Cx55.5 and Cx52.6 gene expression in horizontal cells of adult zebrafish revealed that both Cx55.5 and Cx52.6 contribute to hemichannel currents; however, Cx55.5 expression is necessary for high-amplitude currents. Similarly, coexpression of Cx55.5 with Cx52.6 in oocytes increased hemichannel currents in a supra-additive manner. Taken together these results demonstrate that zebrafish horizontal cell hemichannel currents exhibit the functional characteristics necessary to contribute to synaptic feedback at the first visual synapse, that both Cx55.5 and Cx52.6 contribute to hemichannel currents, and that Cx55.5 may have an additional regulatory function enhancing the amplitude of hemichannel currents.
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MeSH Terms
Structure-function analysis of endogenous lectin mind-the-gap in synaptogenesis.
Rushton E, Rohrbough J, Deutsch K, Broadie K
(2012) Dev Neurobiol 72: 1161-79
MeSH Terms: Amino Acid Sequence, Animals, Animals, Genetically Modified, Carrier Proteins, Drosophila, Drosophila Proteins, Gap Junctions, Gene Knockout Techniques, Lectins, Molecular Sequence Data, Neuromuscular Junction, Structure-Activity Relationship, Synapses
Show Abstract · Added March 29, 2017
Mind-the-Gap (MTG) is required for neuronal induction of Drosophila neuromuscular junction (NMJ) postsynaptic domains, including glutamate receptor (GluR) localization. We have previously hypothesized that MTG is secreted from the presynaptic terminal to reside in the synaptic cleft, where it binds glycans to organize the heavily glycosylated, extracellular synaptomatrix required for transsynaptic signaling between neuron and muscle. In this study, we test this hypothesis with MTG structure-function analyses of predicted signal peptide (SP) and carbohydrate-binding domain (CBD), by introducing deletion and point-mutant transgenic constructs into mtg null mutants. We show that the SP is required for MTG secretion and localization to synapses in vivo. We further show that the CBD is required to restrict MTG diffusion in the extracellular synaptomatrix and for postembryonic viability. However, CBD mutation results in elevation of postsynaptic GluR localization during synaptogenesis, not the mtg null mutant phenotype of reduced GluRs as predicted by our hypothesis, suggesting that proper synaptic localization of MTG limits GluR recruitment. In further testing CBD requirements, we show that MTG binds N-acetylglucosamine (GlcNAc) in a Ca(2+)-dependent manner, and thereby binds HRP-epitope glycans, but that these carbohydrate interactions do not require the CBD. We conclude that the MTG lectin has both positive and negative binding interactions with glycans in the extracellular synaptic domain, which both facilitate and limit GluR localization during NMJ embryonic synaptogenesis.
Copyright © 2012 Wiley Periodicals, Inc.
1 Communities
1 Members
0 Resources
13 MeSH Terms
Gap junctions and other mechanisms of cell-cell communication regulate basal insulin secretion in the pancreatic islet.
Benninger RK, Head WS, Zhang M, Satin LS, Piston DW
(2011) J Physiol 589: 5453-66
MeSH Terms: Animals, Calcium, Cell Communication, Cells, Cultured, Connexins, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Gap Junctions, Glucose, In Vitro Techniques, Insulin, Insulin Secretion, Insulin-Secreting Cells, Islets of Langerhans, Membrane Potentials, Mice, Mice, Knockout
Show Abstract · Added December 5, 2013
Cell-cell communication in the islet of Langerhans is important for the regulation of insulin secretion. Gap-junctions coordinate oscillations in intracellular free-calcium ([Ca(2+)](i)) and insulin secretion in the islet following elevated glucose. Gap-junctions can also ensure that oscillatory [Ca(2+)](i) ceases when glucose is at a basal levels. We determine the roles of gap-junctions and other cell-cell communication pathways in the suppression of insulin secretion under basal conditions. Metabolic, electrical and insulin secretion levels were measured from islets lacking gap-junction coupling following deletion of connexion36 (Cx36(-/-)), and these results were compared to those obtained using fully isolated β-cells. K(ATP) loss-of-function islets provide a further experimental model to specifically study gap-junction mediated suppression of electrical activity. In isolated β-cells or Cx36(-/-) islets, elevations in [Ca(2+)](i) persisted in a subset of cells even at basal glucose. Isolated β-cells showed elevated insulin secretion at basal glucose; however, insulin secretion from Cx36(-/-) islets was minimally altered. [Ca(2+)](i) was further elevated under basal conditions, but insulin release still suppressed in K(ATP) loss-of-function islets. Forced elevation of cAMP led to PKA-mediated increases in insulin secretion from islets lacking gap-junctions, but not from islets expressing Cx36 gap junctions. We conclude there is a redundancy in how cell-cell communication in the islet suppresses insulin release. Gap junctions suppress cellular heterogeneity and spontaneous [Ca(2+)](i) signals, while other juxtacrine mechanisms, regulated by PKA and glucose, suppress more distal steps in exocytosis. Each mechanism is sufficiently robust to compensate for a loss of the other and still suppress basal insulin secretion.
1 Communities
1 Members
0 Resources
17 MeSH Terms
Zinc modulation of hemi-gap-junction channel currents in retinal horizontal cells.
Sun Z, Zhang DQ, McMahon DG
(2009) J Neurophysiol 101: 1774-80
MeSH Terms: Animals, Bass, Biophysics, Calcium, Cations, Divalent, Cells, Cultured, Cysteine, Dose-Response Relationship, Drug, Electric Stimulation, Gap Junctions, Histidine, Ion Channel Gating, Ion Channels, Membrane Potentials, Neural Inhibition, Patch-Clamp Techniques, Retinal Horizontal Cells, Zinc
Show Abstract · Added March 18, 2020
Hemi-gap-junction (HGJ) channels of retinal horizontal cells (HCs) function as transmembrane ion channels that are modulated by voltage and calcium. As an endogenous retinal neuromodulator, zinc, which is coreleased with glutamate at photoreceptor synapses, plays an important role in shaping visual signals by acting on postsynaptic HCs in vivo. To understand more fully the regulation and function of HC HGJ channels, we examined the effect of Zn(2+) on HGJ channel currents in bass retinal HCs. Hemichannel currents elicited by depolarization in Ca(2+)-free medium and in 1 mM Ca(2+) medium were significantly inhibited by extracellular Zn(2+). The inhibition by Zn(2+) of hemichannel currents was dose dependent with a half-maximum inhibitory concentration of 37 microM. Compared with other divalent cations, Zn(2+) exhibited higher inhibitory potency, with the order being Zn(2+) > Cd(2+) approximately Co(2+) > Ca(2+) > Ba(2+) > Mg(2+). Zn(2+) and Ca(2+) were found to modulate HGJ channels independently in additivity experiments. Modification of histidine residues with N-bromosuccinimide suppressed the inhibitory action of Zn(2+), whereas modification of cysteine residues had no significant effect on Zn(2+) inhibition. Taken together, these results suggest that zinc acts on HGJ channels in a calcium-independent way and that histidine residues on the extracellular domain of HGJ channels mediate the inhibitory action of zinc.
0 Communities
1 Members
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MeSH Terms
Gap junction coupling and calcium waves in the pancreatic islet.
Benninger RK, Zhang M, Head WS, Satin LS, Piston DW
(2008) Biophys J 95: 5048-61
MeSH Terms: Animals, Calcium, Calcium Signaling, Cattle, Electricity, Gap Junctions, Gene Knockout Techniques, Insulin-Secreting Cells, Islets of Langerhans, Mice, Models, Biological
Show Abstract · Added August 22, 2011
The pancreatic islet is a highly coupled, multicellular system that exhibits complex spatiotemporal electrical activity in response to elevated glucose levels. The emergent properties of islets, which differ from those arising in isolated islet cells, are believed to arise in part by gap junctional coupling, but the mechanisms through which this coupling occurs are poorly understood. To uncover these mechanisms, we have used both high-speed imaging and theoretical modeling of the electrical activity in pancreatic islets under a reduction in the gap junction mediated electrical coupling. Utilizing islets from a gap junction protein connexin 36 knockout mouse model together with chemical inhibitors, we can modulate the electrical coupling in the islet in a precise manner and quantify this modulation by electrophysiology measurements. We find that after a reduction in electrical coupling, calcium waves are slowed as well as disrupted, and the number of cells showing synchronous calcium oscillations is reduced. This behavior can be reproduced by computational modeling of a heterogeneous population of beta-cells with heterogeneous levels of electrical coupling. The resulting quantitative agreement between the data and analytical models of islet connectivity, using only a single free parameter, reveals the mechanistic underpinnings of the multicellular behavior of the islet.
1 Communities
1 Members
0 Resources
11 MeSH Terms
Nonantiarrhythmic drug therapy for atrial fibrillation.
Murray KT, Mace LC, Yang Z
(2007) Heart Rhythm 4: S88-90
MeSH Terms: Angiotensin II Type 1 Receptor Blockers, Angiotensin-Converting Enzyme Inhibitors, Animals, Anti-Arrhythmia Agents, Anti-Inflammatory Agents, Antioxidants, Atrial Fibrillation, Calcium Channel Blockers, Connexins, Drugs, Investigational, Fatty Acids, Omega-3, Gap Junctions, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Mineralocorticoid Receptor Antagonists, Oligopeptides, Oxidative Stress, Receptors, Serotonin, 5-HT4, Renin-Angiotensin System, Serotonin 5-HT4 Receptor Antagonists, Serotonin Antagonists
Show Abstract · Added January 20, 2015
Recent studies have begun to elucidate the molecular mechanisms that promote the generation and progressive nature of atrial fibrillation. Evidence from both experimental and clinical investigations has implicated an important role for the renin-angiotensin-aldosterone system, inflammation, and oxidative stress, with data that suggest a potential beneficial effect for angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aldosterone receptor antagonists, antiinflammatory agents, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), and omega-3 polyunsaturated fatty acids. In addition, compounds that increase gap junctional conductance or that block 5-hydroxytryptamine-4 receptors have also shown promise in the experimental setting. Large-scale, prospective clinical trials will clarify the utility of these new therapeutic approaches to prevent atrial fibrillation in specific clinical settings.
0 Communities
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21 MeSH Terms