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Article ; Online: Cellular functions of transient receptor potential channels.

Dadon, Daniela / Minke, Baruch

The international journal of biochemistry & cell biology

2010 Volume 42, Issue 9, Page(s) 1430–1445

Abstract: Transient Receptor Potential channels are polymodal cellular sensors involved in a wide variety of cellular processes, mainly by increasing cellular Ca(2+). In this review we focus on the roles of these channels in: (i) cell death (ii) proliferation and ... ...

Abstract	Transient Receptor Potential channels are polymodal cellular sensors involved in a wide variety of cellular processes, mainly by increasing cellular Ca(2+). In this review we focus on the roles of these channels in: (i) cell death (ii) proliferation and differentiation and (iii) transmitter release. Cell death: Ca(2+) influx participates in apoptotic and necrotic cell death. The Ca(2+) permeability and high sensitivity of part of these channels to oxidative/metabolic stress make them important participants in cell death. Several examples are given. Transient Receptor Potential Melastatin 2 is activated by H(2)O(2), inducing cell death through an increase in cellular Ca(2+) and activation of Poly ADP-Ribose Polymerase. Exposure of cultured cortical neurons to oxygen-glucose deprivation, in vitro, causes cell death via cation influx, mediated by Transient Receptor Potential Melastatin 7. Metabolic stress constitutively activates the Ca(2+) permeable Transient Receptor Potential channels of Drosophila photoreceptor in the dark, potentially leading to retinal degeneration. Similar sensitivity to metabolic stress characterizes several mammalian Transient Receptor Potential Canonical channels. Proliferation and differentiation: The rise in cytosolic Ca(2+) induces cell growth, differentiation and proliferation via activation of several transcription factors. Activating a variety of store operated and Transient Receptor Potential channels cause a rise in cytosolic Ca(2+), making these channels components involved in proliferation and differentiation. Transmitter release: Transient Receptor Potential Melastatin 7 channels reside in synaptic vesicles and regulate neurotransmitter release by a mechanism that is not entirely clear. All the above features of Transient Receptor Potential channels make them crucial components in important, sometimes conflicting, cellular processes that still need to be explored.
MeSH term(s)	Animals ; Calcium/metabolism ; Cell Death/genetics ; Cell Death/physiology ; Cell Differentiation/genetics ; Cell Differentiation/physiology ; Cell Proliferation ; Humans ; Models, Biological ; Synaptic Vesicles/metabolism ; Transient Receptor Potential Channels/genetics ; Transient Receptor Potential Channels/metabolism
Chemical Substances	Transient Receptor Potential Channels ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2010-04-22
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1228429-4
ISSN	1878-5875 ; 1357-2725
ISSN (online)	1878-5875
ISSN	1357-2725
DOI	10.1016/j.biocel.2010.04.006
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Zs.A 431: Show issues

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Article ; Online: VDAC1 is a molecular target in glioblastoma, with its depletion leading to reprogrammed metabolism and reversed oncogenic properties.

Arif, Tasleem / Krelin, Yakov / Nakdimon, Itay / Benharroch, Daniel / Paul, Avijit / Dadon-Klein, Daniela / Shoshan-Barmatz, Varda

Neuro-oncology

2017 Volume 19, Issue 7, Page(s) 951–964

Abstract: Background: Glioblastoma (GBM), an aggressive brain tumor with frequent relapses and a high mortality, still awaits an effective treatment. Like many cancers, GBM cells acquire oncogenic properties, including metabolic reprogramming, vital for growth. ... ...

Abstract	Background: Glioblastoma (GBM), an aggressive brain tumor with frequent relapses and a high mortality, still awaits an effective treatment. Like many cancers, GBM cells acquire oncogenic properties, including metabolic reprogramming, vital for growth. As such, tumor metabolism is an emerging avenue for cancer therapy. One relevant target is the voltage-dependent anion channel 1 (VDAC1), a mitochondrial protein controlling cell energy and metabolic homeostasis. Methods: We used VDAC1-specific short interfering (si)RNA (si-VDAC1) to treat GBM cell lines and subcutaneous or intracranial-orthotopic GBM xenograft mouse models. Tumors were monitored using MRI, immunohistochemistry, immunoblotting, immunofluorescence, quantitative real-time PCR, transcription factor expression, and DNA microarray analyses. Results: Silencing VDAC1 expression using si-VDAC1 in 9 glioblastoma-related cell lines, including patient-derived cells, led to marked decreases in VDAC1 levels and cell growth. Using si-VDAC1 in subcutaneous or intracranial-orthotopic GBM models inhibited tumor growth and reversed oncogenic properties, such as reprogrammed metabolism, stemness, angiogenesis, epithelial-mesenchymal transition, and invasiveness. In cells in culture, si-VDAC1 inhibits cancer neurosphere formation and, in tumors, targeted cancer stem cells, leading to their differentiation into neuronal-like cells. These VDAC1 depletion-mediated effects involved alterations in transcription factors regulating signaling pathways associated with cancer hallmarks. Conclusion: VDAC1 offers a target for GBM treatment, allowing for attacks on the interplay between metabolism and oncogenic signaling networks, leading to tumor cell differentiation into neuron- and astrocyte-like cells. Simultaneously attacking all of these processes, VDAC1 depletion overcame GBM heterogeneity and can replace several anticancer drugs that separately target angiogenesis, proliferation, or metabolism.
MeSH term(s)	Animals ; Brain Neoplasms/genetics ; Brain Neoplasms/metabolism ; Brain Neoplasms/therapy ; Cell Line, Tumor ; Cell Proliferation ; Gene Expression ; Glioblastoma/genetics ; Glioblastoma/metabolism ; Glioblastoma/therapy ; Humans ; Male ; Mice, Nude ; RNA, Small Interfering/administration & dosage ; Transcriptome ; Voltage-Dependent Anion Channel 1/antagonists & inhibitors ; Xenograft Model Antitumor Assays
Chemical Substances	RNA, Small Interfering ; VDAC1 protein, human ; Voltage-Dependent Anion Channel 1 (EC 1.6.-)
Language	English
Publishing date	2017-03-20
Publishing country	England
Document type	Journal Article
ZDB-ID	2028601-6
ISSN	1523-5866 ; 1522-8517
ISSN (online)	1523-5866
ISSN	1522-8517
DOI	10.1093/neuonc/now297
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Zs.A 5307: Show issues

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Article ; Online: Hyperglycaemia induces metabolic dysfunction and glycogen accumulation in pancreatic β-cells.

Brereton, Melissa F / Rohm, Maria / Shimomura, Kenju / Holland, Christian / Tornovsky-Babeay, Sharona / Dadon, Daniela / Iberl, Michaela / Chibalina, Margarita V / Lee, Sheena / Glaser, Benjamin / Dor, Yuval / Rorsman, Patrik / Clark, Anne / Ashcroft, Frances M

Nature communications

2016 Volume 7, Page(s) 13496

Abstract: Insulin secretion from pancreatic β-cells is impaired in all forms of diabetes. The resultant hyperglycaemia has deleterious effects on many tissues, including β-cells. Here we show that chronic hyperglycaemia impairs glucose metabolism and alters ... ...

Abstract	Insulin secretion from pancreatic β-cells is impaired in all forms of diabetes. The resultant hyperglycaemia has deleterious effects on many tissues, including β-cells. Here we show that chronic hyperglycaemia impairs glucose metabolism and alters expression of metabolic genes in pancreatic islets. In a mouse model of human neonatal diabetes, hyperglycaemia results in marked glycogen accumulation, and increased apoptosis in β-cells. Sulphonylurea therapy rapidly normalizes blood glucose levels, dissipates glycogen stores, increases autophagy and restores β-cell metabolism. Insulin therapy has the same effect but with slower kinetics. Similar changes are observed in mice expressing an activating glucokinase mutation, in in vitro models of hyperglycaemia, and in islets from type-2 diabetic patients. Altered β-cell metabolism may underlie both the progressive impairment of insulin secretion and reduced β-cell mass in diabetes.
MeSH term(s)	Animals ; Apoptosis/drug effects ; Apoptosis/physiology ; Autophagy/drug effects ; Autophagy/physiology ; Blood Glucose/drug effects ; Blood Glucose/metabolism ; Cell Line ; Diabetes Mellitus, Type 2/metabolism ; Disease Models, Animal ; Glucokinase/genetics ; Glycogen/metabolism ; Humans ; Hyperglycemia/metabolism ; Hypoglycemic Agents/pharmacology ; In Vitro Techniques ; Infant, Newborn ; Infant, Newborn, Diseases/metabolism ; Insulin/pharmacology ; Insulin-Secreting Cells/drug effects ; Insulin-Secreting Cells/metabolism ; Mice ; Mutation ; Rats ; Sulfonylurea Compounds/pharmacology
Chemical Substances	Blood Glucose ; Hypoglycemic Agents ; Insulin ; Sulfonylurea Compounds ; Glycogen (9005-79-2) ; Glucokinase (EC 2.7.1.2)
Language	English
Publishing date	2016-11-24
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/ncomms13496
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Article ; Online: Carvacrol is a novel inhibitor of Drosophila TRPL and mammalian TRPM7 channels.

Parnas, Moshe / Peters, Maximilian / Dadon, Daniela / Lev, Shaya / Vertkin, Irena / Slutsky, Inna / Minke, Baruch

Cell calcium

2009 Volume 45, Issue 3, Page(s) 300–309

Abstract: Transient receptor potential (TRP) channels are essential components of biological sensors that detect changes in the environment in response to a myriad of stimuli. A major difficulty in the study of TRP channels is the lack of pharmacological agents ... ...

Abstract	Transient receptor potential (TRP) channels are essential components of biological sensors that detect changes in the environment in response to a myriad of stimuli. A major difficulty in the study of TRP channels is the lack of pharmacological agents that modulate most members of the TRP superfamily. Notable exceptions are the thermoTRPs, which respond to either cold or hot temperatures and are modulated by a relatively large number of chemical agents. In the present study we demonstrate by patch clamp whole cell recordings from Schneider 2 and Drosophila photoreceptor cells that carvacrol, a known activator of the thermoTRPs, TRPV3 and TRPA1 is an inhibitor of the Drosophila TRPL channels, which belongs to the TRPC subfamily. We also show that additional activators of TRPV3, thymol, eugenol, cinnamaldehyde and menthol are all inhibitors of the TRPL channel. Furthermore, carvacrol also inhibits the mammalian TRPM7 heterologously expressed in HEK cells and ectopically expressed in a primary culture of CA3-CA1 hippocampal brain neurons. This study, thus, identifies a novel inhibitor of TRPC and TRPM channels. Our finding that the activity of the non-thermoTRPs, TRPL and TRPM7 channels is modulated by the same compound as thermoTRPs, suggests that common mechanisms of channel modulation characterize TRP channels.
MeSH term(s)	Acrolein/analogs & derivatives ; Acrolein/chemistry ; Acrolein/pharmacology ; Animals ; Camphanes/chemistry ; Camphanes/pharmacology ; Cells, Cultured ; Cyclohexane Monoterpenes ; Cymenes ; Drosophila Proteins/antagonists & inhibitors ; Drosophila melanogaster/metabolism ; Eugenol/chemistry ; Eugenol/pharmacology ; Hippocampus/cytology ; Humans ; Mammals/metabolism ; Menthol/chemistry ; Menthol/pharmacology ; Monoterpenes/chemistry ; Monoterpenes/pharmacology ; Neurons/drug effects ; Neurons/metabolism ; Photoreceptor Cells, Invertebrate/cytology ; Photoreceptor Cells, Invertebrate/drug effects ; Photoreceptor Cells, Invertebrate/metabolism ; Protein-Serine-Threonine Kinases ; TRPM Cation Channels/antagonists & inhibitors ; Thymol/chemistry ; Thymol/pharmacology ; Transient Receptor Potential Channels/antagonists & inhibitors
Chemical Substances	Camphanes ; Cyclohexane Monoterpenes ; Cymenes ; Drosophila Proteins ; Monoterpenes ; TRPM Cation Channels ; Transient Receptor Potential Channels ; trpl protein, Drosophila ; Menthol (1490-04-6) ; Thymol (3J50XA376E) ; Eugenol (3T8H1794QW) ; Acrolein (7864XYD3JJ) ; carveol (99-48-9) ; carvacrol (9B1J4V995Q) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; TRPM7 protein, human (EC 2.7.11.1) ; isoborneol (L88RA8N5EG) ; cinnamaldehyde (SR60A3XG0F)
Language	English
Publishing date	2009-01-09
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	757687-0
ISSN	1532-1991 ; 0143-4160
ISSN (online)	1532-1991
ISSN	0143-4160
DOI	10.1016/j.ceca.2008.11.009
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Zs.A 1596: Show issues

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Article ; Online: Compartmentalization and Ca2+ buffering are essential for prevention of light-induced retinal degeneration.

Weiss, Shirley / Kohn, Elkana / Dadon, Daniela / Katz, Ben / Peters, Maximilian / Lebendiker, Mario / Kosloff, Mickey / Colley, Nansi Jo / Minke, Baruch

The Journal of neuroscience : the official journal of the Society for Neuroscience

2012 Volume 32, Issue 42, Page(s) 14696–14708

Abstract: Fly photoreceptors are polarized cells, each of which has an extended interface between its cell body and the light-signaling compartment, the rhabdomere. Upon intense illumination, rhabdomeric calcium concentration reaches millimolar levels that would ... ...

Abstract	Fly photoreceptors are polarized cells, each of which has an extended interface between its cell body and the light-signaling compartment, the rhabdomere. Upon intense illumination, rhabdomeric calcium concentration reaches millimolar levels that would be toxic if Ca(2+) diffusion between the rhabdomere and cell body was not robustly attenuated. Yet, it is not clear how such effective attenuation is obtained. Here we show that Ca(2+) homeostasis in the photoreceptor cell relies on the protein calphotin. This unique protein functions as an immobile Ca(2+) buffer localized along the base of the rhabdomere, separating the signaling compartment from the cell body. Generation and analyses of transgenic Drosophila strains, in which calphotin-expression levels were reduced in a graded manner, showed that moderately reduced calphotin expression impaired Ca(2+) homeostasis while calphotin elimination resulted in severe light-dependent photoreceptor degeneration. Electron microscopy, electrophysiology, and optical methods revealed that the degeneration was rescued by prevention of Ca(2+) overload via overexpression of CalX, the Na(+)-Ca(2+) exchanger. In addition, Ca(2+)-imaging experiments showed that reduced calphotin levels resulted in abnormally fast kinetics of Ca(2+) elevation in photoreceptor cells. Together, the data suggest that calphotin functions as a Ca(2+) buffer; a possibility that we directly demonstrate by expressing calphotin in a heterologous expression system. We propose that calphotin-mediated compartmentalization and Ca(2+) buffering constitute an effective strategy to protect cells from Ca(2+) overload and light-induced degeneration.
MeSH term(s)	Animals ; Animals, Genetically Modified ; Buffers ; Calcium/metabolism ; Calcium-Binding Proteins/physiology ; Cell Compartmentation/physiology ; Dark Adaptation/physiology ; Drosophila Proteins/physiology ; Drosophila melanogaster ; HEK293 Cells ; Humans ; Hydrogen-Ion Concentration ; Light/adverse effects ; Photoreceptor Cells, Invertebrate/metabolism ; Photoreceptor Cells, Invertebrate/pathology ; Retinal Degeneration/etiology ; Retinal Degeneration/pathology ; Retinal Degeneration/prevention & control
Chemical Substances	Buffers ; Calcium-Binding Proteins ; Cpn protein, Drosophila ; Drosophila Proteins ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2012-10-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.2456-12.2012
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Zs.A 1668: Show issues

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Article ; Online: Hyperglycaemia induces metabolic dysfunction and glycogen accumulation in pancreatic β-cells

Melissa F. Brereton / Maria Rohm / Kenju Shimomura / Christian Holland / Sharona Tornovsky-Babeay / Daniela Dadon / Michaela Iberl / Margarita V. Chibalina / Sheena Lee / Benjamin Glaser / Yuval Dor / Patrik Rorsman / Anne Clark / Frances M. Ashcroft

Nature Communications, Vol 7, Iss 1, Pp 1-

2016 Volume 15

Abstract: Diabetes is characterized by prolonged hyperglycaemia and tissue damage in pancreatic islets. Here, Brereton et al. show that chronic high glucose levels lead to glycogen accumulation in β-cells, associated with reduced autophagy, impaired metabolism, ... ...

Abstract	Diabetes is characterized by prolonged hyperglycaemia and tissue damage in pancreatic islets. Here, Brereton et al. show that chronic high glucose levels lead to glycogen accumulation in β-cells, associated with reduced autophagy, impaired metabolism, insulin granule depletion and apoptosis.
Keywords	Science ; Q
Language	English
Publishing date	2016-11-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
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Article ; Online: Membrane lipid modulations remove divalent open channel block from TRP-like and NMDA channels.

Parnas, Moshe / Katz, Ben / Lev, Shaya / Tzarfaty, Vered / Dadon, Daniela / Gordon-Shaag, Ariela / Metzner, Henry / Yaka, Rami / Minke, Baruch

The Journal of neuroscience : the official journal of the Society for Neuroscience

2009 Volume 29, Issue 8, Page(s) 2371–2383

Abstract: Open channel block is a process in which ions bound to the inside of a channel pore block the flow of ions through that channel. Repulsion of the blocking ions by depolarization is a known mechanism of open channel block removal. For the NMDA channel, ... ...

Abstract	Open channel block is a process in which ions bound to the inside of a channel pore block the flow of ions through that channel. Repulsion of the blocking ions by depolarization is a known mechanism of open channel block removal. For the NMDA channel, this mechanism is necessary for channel activation and is involved in neuronal plasticity. Several types of transient receptor potential (TRP) channels, including the Drosophila TRP and TRP-like (TRPL) channels, also exhibit open channel block. Therefore, removal of open channel block is necessary for the production of the physiological response to light. Because there is no membrane depolarization before the light response develops, it is not clear how the open channel block is removed, an essential step for the production of a robust light response under physiological conditions. Here we present a novel mechanism to alleviate open channel block in the absence of depolarization by membrane lipid modulations. The results of this study show open channel block removal by membrane lipid modulations in both TRPL and NMDA channels of the photoreceptor cells and CA1 hippocampal neurons, respectively. Removal of open channel block is characterized by an increase in the passage-rate of the blocking cations through the channel pore. We propose that the profound effect of membrane lipid modulations on open channel block alleviation, allows the productions of a robust current in response to light in the absence of depolarization.
MeSH term(s)	Animals ; Animals, Genetically Modified ; Biophysics ; Calcium/pharmacology ; Cells, Cultured ; Dose-Response Relationship, Drug ; Drosophila ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Electric Stimulation ; Green Fluorescent Proteins/genetics ; Hippocampus/cytology ; In Vitro Techniques ; Ion Channel Gating/drug effects ; Ion Channel Gating/genetics ; Ion Channel Gating/physiology ; Light ; Linoleic Acid/pharmacology ; Magnesium/pharmacology ; Membrane Lipids/pharmacology ; Membrane Potentials/drug effects ; Membrane Potentials/genetics ; Mutation/genetics ; N-Methylaspartate/pharmacology ; Neurons/drug effects ; Neurons/physiology ; Patch-Clamp Techniques/methods ; Photoreceptor Cells, Invertebrate/metabolism ; Rats ; Receptors, N-Methyl-D-Aspartate/genetics ; Receptors, N-Methyl-D-Aspartate/physiology ; Transient Receptor Potential Channels/genetics ; Transient Receptor Potential Channels/physiology
Chemical Substances	Drosophila Proteins ; Membrane Lipids ; Receptors, N-Methyl-D-Aspartate ; Transient Receptor Potential Channels ; enhanced green fluorescent protein ; Green Fluorescent Proteins (147336-22-9) ; N-Methylaspartate (6384-92-5) ; Linoleic Acid (9KJL21T0QJ) ; Magnesium (I38ZP9992A) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2009-02-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	604637-x
ISSN	1529-2401 ; 0270-6474
ISSN (online)	1529-2401
ISSN	0270-6474
DOI	10.1523/JNEUROSCI.4280-08.2009
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Zs.A 1668: Show issues

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Article ; Online: Type 2 diabetes and congenital hyperinsulinism cause DNA double-strand breaks and p53 activity in β cells.

Cell metabolism

2013 Volume 19, Issue 1, Page(s) 109–121

Abstract: β cell failure in type 2 diabetes (T2D) is associated with hyperglycemia, but the mechanisms are not fully understood. Congenital hyperinsulinism caused by glucokinase mutations (GCK-CHI) is associated with β cell replication and apoptosis. Here, we show ...

Abstract	β cell failure in type 2 diabetes (T2D) is associated with hyperglycemia, but the mechanisms are not fully understood. Congenital hyperinsulinism caused by glucokinase mutations (GCK-CHI) is associated with β cell replication and apoptosis. Here, we show that genetic activation of β cell glucokinase, initially triggering replication, causes apoptosis associated with DNA double-strand breaks and activation of the tumor suppressor p53. ATP-sensitive potassium channels (KATP channels) and calcineurin mediate this toxic effect. Toxicity of long-term glucokinase overactivity was confirmed by finding late-onset diabetes in older members of a GCK-CHI family. Glucagon-like peptide-1 (GLP-1) mimetic treatment or p53 deletion rescues β cells from glucokinase-induced death, but only GLP-1 analog rescues β cell function. DNA damage and p53 activity in T2D suggest shared mechanisms of β cell failure in hyperglycemia and CHI. Our results reveal membrane depolarization via KATP channels, calcineurin signaling, DNA breaks, and p53 as determinants of β cell glucotoxicity and suggest pharmacological approaches to enhance β cell survival in diabetes.
MeSH term(s)	Animals ; Biomarkers/metabolism ; Calcineurin/metabolism ; Cell Death/drug effects ; Cell Proliferation/drug effects ; Congenital Hyperinsulinism/complications ; Congenital Hyperinsulinism/enzymology ; Congenital Hyperinsulinism/pathology ; DNA Breaks, Double-Stranded/drug effects ; Diabetes Mellitus, Type 2/complications ; Diabetes Mellitus, Type 2/enzymology ; Diabetes Mellitus, Type 2/pathology ; Disease Models, Animal ; Enzyme Activation/drug effects ; Enzyme Induction/drug effects ; Fasting/metabolism ; Glucagon-Like Peptide 1/pharmacology ; Glucokinase/biosynthesis ; Glucose/toxicity ; Humans ; Insulin-Secreting Cells/drug effects ; Insulin-Secreting Cells/enzymology ; Insulin-Secreting Cells/metabolism ; Insulin-Secreting Cells/pathology ; Membrane Potentials/drug effects ; Mice ; Transgenes ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	Biomarkers ; Tumor Suppressor Protein p53 ; Glucagon-Like Peptide 1 (89750-14-1) ; Glucokinase (EC 2.7.1.2) ; Calcineurin (EC 3.1.3.16) ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2013-12-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2176834-1
ISSN	1932-7420 ; 1550-4131
ISSN (online)	1932-7420
ISSN	1550-4131
DOI	10.1016/j.cmet.2013.11.007
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Zs.A 6169: Show issues

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Article ; Online: Control of pancreatic β cell regeneration by glucose metabolism.

Porat, Shay / Weinberg-Corem, Noa / Tornovsky-Babaey, Sharona / Schyr-Ben-Haroush, Rachel / Hija, Ayat / Stolovich-Rain, Miri / Dadon, Daniela / Granot, Zvi / Ben-Hur, Vered / White, Peter / Girard, Christophe A / Karni, Rotem / Kaestner, Klaus H / Ashcroft, Frances M / Magnuson, Mark A / Saada, Ann / Grimsby, Joseph / Glaser, Benjamin / Dor, Yuval

Cell metabolism

2011 Volume 13, Issue 4, Page(s) 440–449

Abstract: Recent studies revealed a surprising regenerative capacity of insulin-producing β cells in mice, suggesting that regenerative therapy for human diabetes could in principle be achieved. Physiologic β cell regeneration under stressed conditions relies on ... ...

Abstract	Recent studies revealed a surprising regenerative capacity of insulin-producing β cells in mice, suggesting that regenerative therapy for human diabetes could in principle be achieved. Physiologic β cell regeneration under stressed conditions relies on accelerated proliferation of surviving β cells, but the factors that trigger and control this response remain unclear. Using islet transplantation experiments, we show that β cell mass is controlled systemically rather than by local factors such as tissue damage. Chronic changes in β cell glucose metabolism, rather than blood glucose levels per se, are the main positive regulator of basal and compensatory β cell proliferation in vivo. Intracellularly, genetic and pharmacologic manipulations reveal that glucose induces β cell replication via metabolism by glucokinase, the first step of glycolysis, followed by closure of K(ATP) channels and membrane depolarization. Our data provide a molecular mechanism for homeostatic control of β cell mass by metabolic demand.
MeSH term(s)	Animals ; Blood Glucose/metabolism ; Cell Membrane/physiology ; Cell Proliferation ; Glucokinase/antagonists & inhibitors ; Glucokinase/metabolism ; Glycolysis ; Insulin-Secreting Cells/metabolism ; Insulin-Secreting Cells/physiology ; Insulin-Secreting Cells/transplantation ; KATP Channels/metabolism ; Mice ; Regeneration
Chemical Substances	Blood Glucose ; KATP Channels ; Glucokinase (EC 2.7.1.2)
Language	English
Publishing date	2011-04-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2176834-1
ISSN	1932-7420 ; 1550-4131
ISSN (online)	1932-7420
ISSN	1550-4131
DOI	10.1016/j.cmet.2011.02.012
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Article: Control of Pancreatic β Cell Regeneration by Glucose Metabolism

Cell metabolism. 2011 Apr. 6, v. 13, no. 4

2011

Abstract	Recent studies revealed a surprising regenerative capacity of insulin-producing β cells in mice, suggesting that regenerative therapy for human diabetes could in principle be achieved. Physiologic β cell regeneration under stressed conditions relies on accelerated proliferation of surviving β cells, but the factors that trigger and control this response remain unclear. Using islet transplantation experiments, we show that β cell mass is controlled systemically rather than by local factors such as tissue damage. Chronic changes in β cell glucose metabolism, rather than blood glucose levels per se, are the main positive regulator of basal and compensatory β cell proliferation in vivo. Intracellularly, genetic and pharmacologic manipulations reveal that glucose induces β cell replication via metabolism by glucokinase, the first step of glycolysis, followed by closure of KATP channels and membrane depolarization. Our data provide a molecular mechanism for homeostatic control of β cell mass by metabolic demand.
Keywords	blood glucose ; cell proliferation ; diabetes ; glucokinase ; glucose ; glycolysis ; humans ; mice ; therapeutics
Language	English
Dates of publication	2011-0406
Size	p. 440-449.
Publishing place	Elsevier Inc.
Document type	Article
ZDB-ID	2176834-1
ISSN	1932-7420 ; 1550-4131
ISSN (online)	1932-7420
ISSN	1550-4131
DOI	10.1016/j.cmet.2011.02.012
Database	NAL-Catalogue (AGRICOLA)

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