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Excitotoxicity and Overnutrition Additively Impair Metabolic Function and Identity of Pancreatic β-Cells.
Osipovich AB, Stancill JS, Cartailler JP, Dudek KD, Magnuson MA
(2020) Diabetes 69: 1476-1491
MeSH Terms: Animals, Calcium, Cells, Cultured, Diet, High-Fat, Female, Gene Expression Regulation, Glucose, Insulin-Secreting Cells, Male, Mice, Mice, Inbred C57BL, Mitochondria, Overnutrition, Sex Characteristics, Transcriptome
Show Abstract · Added April 28, 2020
A sustained increase in intracellular Ca concentration (referred to hereafter as excitotoxicity), brought on by chronic metabolic stress, may contribute to pancreatic β-cell failure. To determine the additive effects of excitotoxicity and overnutrition on β-cell function and gene expression, we analyzed the impact of a high-fat diet (HFD) on knockout mice. Excitotoxicity caused β-cells to be more susceptible to HFD-induced impairment of glucose homeostasis, and these effects were mitigated by verapamil, a Ca channel blocker. Excitotoxicity, overnutrition, and the combination of both stresses caused similar but distinct alterations in the β-cell transcriptome, including additive increases in genes associated with mitochondrial energy metabolism, fatty acid β-oxidation, and mitochondrial biogenesis and their key regulator Overnutrition worsened excitotoxicity-induced mitochondrial dysfunction, increasing metabolic inflexibility and mitochondrial damage. In addition, excitotoxicity and overnutrition, individually and together, impaired both β-cell function and identity by reducing expression of genes important for insulin secretion, cell polarity, cell junction, cilia, cytoskeleton, vesicular trafficking, and regulation of β-cell epigenetic and transcriptional program. Sex had an impact on all β-cell responses, with male animals exhibiting greater metabolic stress-induced impairments than females. Together, these findings indicate that a sustained increase in intracellular Ca, by altering mitochondrial function and impairing β-cell identity, augments overnutrition-induced β-cell failure.
© 2020 by the American Diabetes Association.
2 Communities
3 Members
0 Resources
15 MeSH Terms
Coregulator Sin3a Promotes Postnatal Murine β-Cell Fitness by Regulating Genes in Ca Homeostasis, Cell Survival, Vesicle Biosynthesis, Glucose Metabolism, and Stress Response.
Yang X, Graff SM, Heiser CN, Ho KH, Chen B, Simmons AJ, Southard-Smith AN, David G, Jacobson DA, Kaverina I, Wright CVE, Lau KS, Gu G
(2020) Diabetes 69: 1219-1231
MeSH Terms: Aging, Animals, Basic Helix-Loop-Helix Transcription Factors, Calcium, Cell Survival, Diabetes Mellitus, Female, Gene Expression Regulation, Developmental, Homeostasis, Insulin-Secreting Cells, Male, Mice, Mice, Knockout, Nerve Tissue Proteins, Repressor Proteins, Sin3 Histone Deacetylase and Corepressor Complex
Show Abstract · Added April 7, 2020
Swi-independent 3a and 3b (Sin3a and Sin3b) are paralogous transcriptional coregulators that direct cellular differentiation, survival, and function. Here, we report that mouse Sin3a and Sin3b are coproduced in most pancreatic cells during embryogenesis but become much more enriched in endocrine cells in adults, implying continued essential roles in mature endocrine cell function. Mice with loss of in endocrine progenitors were normal during early postnatal stages but gradually developed diabetes before weaning. These physiological defects were preceded by the compromised survival, insulin-vesicle packaging, insulin secretion, and nutrient-induced Ca influx of -deficient β-cells. RNA sequencing coupled with candidate chromatin immunoprecipitation assays revealed several genes that could be directly regulated by Sin3a in β-cells, which modulate Ca/ion transport, cell survival, vesicle/membrane trafficking, glucose metabolism, and stress responses. Finally, mice with loss of both and in multipotent embryonic pancreatic progenitors had significantly reduced islet cell mass at birth, caused by decreased endocrine progenitor production and increased β-cell death. These findings highlight the stage-specific requirements for the presumed "general" coregulators Sin3a and Sin3b in islet β-cells, with Sin3a being dispensable for differentiation but required for postnatal function and survival.
© 2020 by the American Diabetes Association.
2 Communities
2 Members
0 Resources
16 MeSH Terms
Calmodulin Mutations Associated with Heart Arrhythmia: A Status Report.
Chazin WJ, Johnson CN
(2020) Int J Mol Sci 21:
MeSH Terms: Arrhythmias, Cardiac, Calcium Signaling, Calmodulin, Humans, Ion Channels, Long QT Syndrome, Myocytes, Cardiac, Ryanodine Receptor Calcium Release Channel, Tachycardia, Ventricular
Show Abstract · Added March 11, 2020
Calmodulin (CaM) is a ubiquitous intracellular Ca sensing protein that modifies gating of numerous ion channels. CaM has an extraordinarily high level of evolutionary conservation, which led to the fundamental assumption that mutation would be lethal. However, in 2012, complete exome sequencing of infants suffering from recurrent cardiac arrest revealed de novo mutations in the three human genes. The correlation between mutations and pathophysiology suggests defects in CaM-dependent ion channel functions. Here, we review the current state of the field for all reported CaM mutations associated with cardiac arrhythmias, including knowledge of their biochemical and structural characteristics, and progress towards understanding how these mutations affect cardiac ion channel function.
0 Communities
1 Members
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9 MeSH Terms
Identification of a selective manganese ionophore that enables nonlethal quantification of cellular manganese.
Horning KJ, Joshi P, Nitin R, Balachandran RC, Yanko FM, Kim K, Christov P, Aschner M, Sulikowski GA, Weaver CD, Bowman AB
(2020) J Biol Chem 295: 3875-3890
MeSH Terms: Animals, Calcimycin, Calcium, Cell Line, Cell Survival, Fura-2, HEK293 Cells, Humans, Induced Pluripotent Stem Cells, Ionomycin, Ionophores, Male, Manganese, Mass Spectrometry, Mice
Show Abstract · Added March 27, 2020
Available assays for measuring cellular manganese (Mn) levels require cell lysis, restricting longitudinal experiments and multiplexed outcome measures. Conducting a screen of small molecules known to alter cellular Mn levels, we report here that one of these chemicals induces rapid Mn efflux. We describe this activity and the development and implementation of an assay centered on this small molecule, named anganese-xtracting mall olecule (MESM). Using inductively-coupled plasma-MS, we validated that this assay, termed here "anganese-xtracting mall olecule stimation oute" (MESMER), can accurately assess Mn in mammalian cells. Furthermore, we found evidence that MESM acts as a Mn-selective ionophore, and we observed that it has increased rates of Mn membrane transport, reduced cytotoxicity, and increased selectivity for Mn over calcium compared with two established Mn ionophores, calcimycin (A23187) and ionomycin. Finally, we applied MESMER to test whether prior Mn exposures subsequently affect cellular Mn levels. We found that cells receiving continuous, elevated extracellular Mn accumulate less Mn than cells receiving equally-elevated Mn for the first time for 24 h, indicating a compensatory cellular homeostatic response. Use of the MESMER assay a comparable detergent lysis-based assay, cellular Fura-2 Mn extraction assay, reduced the number of cells and materials required for performing a similar but cell lethality-based experiment to 25% of the normally required sample size. We conclude that MESMER can accurately quantify cellular Mn levels in two independent cells lines through an ionophore-based mechanism, maintaining cell viability and enabling longitudinal assessment within the same cultures.
© 2020 Horning et al.
0 Communities
1 Members
0 Resources
15 MeSH Terms
Neuronal L-Type Calcium Channel Signaling to the Nucleus Requires a Novel CaMKIIα-Shank3 Interaction.
Perfitt TL, Wang X, Dickerson MT, Stephenson JR, Nakagawa T, Jacobson DA, Colbran RJ
(2020) J Neurosci 40: 2000-2014
MeSH Terms: Animals, Calcium Channels, L-Type, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Cell Nucleus, Gene Expression Regulation, Hippocampus, Mice, Mice, Inbred C57BL, Microfilament Proteins, Nerve Tissue Proteins, Neurons, Signal Transduction
Show Abstract · Added March 3, 2020
The activation of neuronal plasma membrane Ca channels stimulates many intracellular responses. Scaffolding proteins can preferentially couple specific Ca channels to distinct downstream outputs, such as increased gene expression, but the molecular mechanisms that underlie the exquisite specificity of these signaling pathways are incompletely understood. Here, we show that complexes containing CaMKII and Shank3, a postsynaptic scaffolding protein known to interact with L-type calcium channels (LTCCs), can be specifically coimmunoprecipitated from mouse forebrain extracts. Activated purified CaMKIIα also directly binds Shank3 between residues 829 and 1130. Mutation of Shank3 residues Arg-Arg-Lys to three alanines disrupts CaMKII binding and CaMKII association with Shank3 in heterologous cells. Our shRNA/rescue studies revealed that Shank3 binding to both CaMKII and LTCCs is important for increased phosphorylation of the nuclear CREB transcription factor and expression of c-Fos induced by depolarization of cultured hippocampal neurons. Thus, this novel CaMKII-Shank3 interaction is essential for the initiation of a specific long-range signal from LTCCs in the plasma membrane to the nucleus that is required for activity-dependent changes in neuronal gene expression during learning and memory. Precise neuronal expression of genes is essential for normal brain function. Proteins involved in signaling pathways that underlie activity-dependent gene expression, such as CaMKII, Shank3, and L-type calcium channels, are often mutated in multiple neuropsychiatric disorders. Shank3 and CaMKII were previously shown to bind L-type calcium channels, and we show here that Shank3 also binds to CaMKII. Our data show that each of these interactions is required for depolarization-induced phosphorylation of the CREB nuclear transcription factor, which stimulates the expression of c-Fos, a neuronal immediate early gene with key roles in synaptic plasticity, brain development, and behavior.
Copyright © 2020 the authors.
1 Communities
1 Members
0 Resources
12 MeSH Terms
Cryo-EM structure of human type-3 inositol triphosphate receptor reveals the presence of a self-binding peptide that acts as an antagonist.
Azumaya CM, Linton EA, Risener CJ, Nakagawa T, Karakas E
(2020) J Biol Chem 295: 1743-1753
MeSH Terms: Binding Sites, Calcium Signaling, Cryoelectron Microscopy, Humans, Inositol 1,4,5-Trisphosphate, Inositol 1,4,5-Trisphosphate Receptors, Models, Molecular, Peptides, Protein Conformation
Show Abstract · Added March 3, 2020
Calcium-mediated signaling through inositol 1,4,5-triphosphate receptors (IPRs) is essential for the regulation of numerous physiological processes, including fertilization, muscle contraction, apoptosis, secretion, and synaptic plasticity. Deregulation of IPRs leads to pathological calcium signaling and is implicated in many common diseases, including cancer and neurodegenerative, autoimmune, and metabolic diseases. Revealing the mechanism of activation and inhibition of this ion channel will be critical to an improved understanding of the biological processes that are controlled by IPRs. Here, we report structural findings of the human type-3 IPR (IPR-3) obtained by cryo-EM (at an overall resolution of 3.8 Å), revealing an unanticipated regulatory mechanism where a loop distantly located in the primary sequence occupies the IP-binding site and competitively inhibits IP binding. We propose that this inhibitory mechanism must differ qualitatively among IPR subtypes because of their diverse loop sequences, potentially serving as a key molecular determinant of subtype-specific calcium signaling in IPRs. In summary, our structural characterization of human IPR-3 provides critical insights into the mechanistic function of IPRs and into subtype-specific regulation of these important calcium-regulatory channels.
© 2020 Azumaya et al.
0 Communities
2 Members
0 Resources
9 MeSH Terms
Small Molecule Inhibitor Screen Reveals Calcium Channel Signaling as a Mechanistic Mediator of TcdB-Induced Necrosis.
Farrow MA, Chumber NM, Bloch SC, King M, Moton-Melancon K, Shupe J, Washington MK, Spiller BW, Lacy DB
(2020) ACS Chem Biol 15: 1212-1221
MeSH Terms: Actin Cytoskeleton, Animals, Anti-Infective Agents, Bacterial Toxins, Calcium Channel Blockers, Calcium Channels, Calcium Signaling, Clostridioides difficile, Cytokines, Dihydropyridines, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Glucosyltransferases, Humans, Kinetics, Mice, NADPH Oxidases, Necrosis, Reactive Oxygen Species, Virulence Factors
Show Abstract · Added March 24, 2020
is the leading cause of nosocomial diarrhea in the United States. The primary virulence factors are two homologous glucosyltransferase toxins, TcdA and TcdB, that inactivate host Rho-family GTPases. The glucosyltransferase activity has been linked to a "cytopathic" disruption of the actin cytoskeleton and contributes to the disruption of tight junctions and the production of pro-inflammatory cytokines. TcdB is also a potent cytotoxin that causes epithelium necrotic damage through an NADPH oxidase (NOX)-dependent mechanism. We conducted a small molecule screen to identify compounds that confer protection against TcdB-induced necrosis. We identified an enrichment of "hit compounds" with a dihydropyridine (DHP) core which led to the discovery of a key early stage calcium signal that serves as a mechanistic link between TcdB-induced NOX activation and reactive oxygen species (ROS) production. Disruption of TcdB-induced calcium signaling (with both DHP and non-DHP molecules) is sufficient to ablate ROS production and prevent subsequent necrosis in cells and in a mouse model of intoxication.
0 Communities
2 Members
0 Resources
20 MeSH Terms
Local, nonlinear effects of cGMP and Ca2+ reduce single photon response variability in retinal rods.
Caruso G, Gurevich VV, Klaus C, Hamm H, Makino CL, DiBenedetto E
(2019) PLoS One 14: e0225948
MeSH Terms: Algorithms, Animals, Biomarkers, Calcium, Cyclic GMP, Mice, Models, Biological, Photons, Retinal Rod Photoreceptor Cells, Rod Cell Outer Segment, Signal Transduction
Show Abstract · Added March 18, 2020
The single photon response (SPR) in vertebrate photoreceptors is inherently variable due to several stochastic events in the phototransduction cascade, the main one being the shutoff of photoactivated rhodopsin. Deactivation is driven by a random number of steps, each of random duration with final quenching occurring after a random delay. Nevertheless, variability of the SPR is relatively low, making the signal highly reliable. Several biophysical and mathematical mechanisms contributing to variability suppression have been examined by the authors. Here we investigate the contribution of local depletion of cGMP by PDE*, the non linear dependence of the photocurrent on cGMP, Ca2+ feedback by making use of a fully space resolved (FSR) mathematical model, applied to two species (mouse and salamander), by varying the cGMP diffusion rate severalfold and rod outer segment diameter by an order of magnitude, and by introducing new, more refined, and time dependent variability functionals. Globally well stirred (GWS) models, and to a lesser extent transversally well stirred models (TWS), underestimate the role of nonlinearities and local cGMP depletion in quenching the variability of the circulating current with respect to fully space resolved models (FSR). These distortions minimize the true extent to which SPR is stabilized by locality in cGMP depletion, nonlinear effects linking cGMP to current, and Ca2+ feedback arising from the physical separation of E* from the ion channels located on the outer shell, and the diffusion of these second messengers in the cytoplasm.
0 Communities
1 Members
0 Resources
11 MeSH Terms
Biased M receptor-positive allosteric modulators reveal role of phospholipase D in M-dependent rodent cortical plasticity.
Moran SP, Xiang Z, Doyle CA, Maksymetz J, Lv X, Faltin S, Fisher NM, Niswender CM, Rook JM, Lindsley CW, Conn PJ
(2019) Sci Signal 12:
MeSH Terms: Allosteric Site, Animals, CHO Cells, Calcium, Cerebral Cortex, Cognition, Cricetinae, Cricetulus, Electrophysiology, Female, Humans, Long-Term Synaptic Depression, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Neuronal Plasticity, Phospholipase D, Prefrontal Cortex, Receptor, Muscarinic M1, Signal Transduction, Type C Phospholipases
Show Abstract · Added March 3, 2020
Highly selective, positive allosteric modulators (PAMs) of the M subtype of muscarinic acetylcholine receptor have emerged as an exciting new approach to potentially improve cognitive function in patients suffering from Alzheimer's disease and schizophrenia. Discovery programs have produced a structurally diverse range of M receptor PAMs with distinct pharmacological properties, including different extents of agonist activity and differences in signal bias. This includes biased M receptor PAMs that can potentiate coupling of the receptor to activation of phospholipase C (PLC) but not phospholipase D (PLD). However, little is known about the role of PLD in M receptor signaling in native systems, and it is not clear whether biased M PAMs display differences in modulating M-mediated responses in native tissue. Using PLD inhibitors and PLD knockout mice, we showed that PLD was necessary for the induction of M-dependent long-term depression (LTD) in the prefrontal cortex (PFC). Furthermore, biased M PAMs that did not couple to PLD not only failed to potentiate orthosteric agonist-induced LTD but also blocked M-dependent LTD in the PFC. In contrast, biased and nonbiased M PAMs acted similarly in potentiating M-dependent electrophysiological responses that were PLD independent. These findings demonstrate that PLD plays a critical role in the ability of M PAMs to modulate certain central nervous system (CNS) functions and that biased M PAMs function differently in brain regions implicated in cognition.
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
0 Communities
2 Members
0 Resources
22 MeSH Terms
Physiological roles for neuromodulation via G GPCRs working through Gβγ-SNARE interaction.
Hamm HE, Alford ST
(2020) Neuropsychopharmacology 45: 221
MeSH Terms: Animals, Calcium, GTP-Binding Protein alpha Subunits, Gi-Go, GTP-Binding Protein beta Subunits, GTP-Binding Protein gamma Subunits, Humans, Neurotransmitter Agents, Protein Binding, SNARE Proteins
Added March 24, 2020
0 Communities
1 Members
0 Resources
9 MeSH Terms