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Flood, L., Korol, S., Ekselius, L., Birnir, B. & Jin, Z. (2019). Interferon-gamma potentiates GABA(A) receptor-mediated inhibitory currents in rat hippocampal CA1 pyramidal neurons. Journal of Neuroimmunology, 337, Article ID UNSP 577050.
Open this publication in new window or tab >>Interferon-gamma potentiates GABA(A) receptor-mediated inhibitory currents in rat hippocampal CA1 pyramidal neurons
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2019 (English)In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 337, article id UNSP 577050Article in journal (Refereed) Published
Abstract [en]

The neural transmission and plasticity can be differentially modulated by various elements of the immune system. Interferon-gamma (IFN-gamma) is a "pro-inflammatory" cytokine mainly produced by T lymphocytes, activates its corresponding receptor and plays important roles under both homeostatic and inflammatory conditions. However, the impact of IFN-gamma on the gamma-aminobutyric acid (GABA)-mediated currents in the hippocampus, a major brain region involved in the cognitive function, has not been investigated. Here we detected abundant expression of both IFN-gamma receptor subunit gene transcripts (Ifngrl and Ifngr2) in the rat hippocampus by quantitative PCR. In addition, we pre-incubated rat hippocampal slices with IFN-gamma (100 ng/ml) and recorded GABA-activated spontaneous and miniature postsynaptic inhibitory currents (sIPSCs and mIPSCs) and tonic currents in hippocampal CAl pyramidal neurons by the whole-cell patch-clamp method. The pre-incubation with IFN-gamma increased the frequency but not the mean amplitude, rise time or decay time of both sIPSCs and mIPSCs in hippocampal CAl pyramidal neurons, suggesting a presynaptic effect of IFN-gamma. Moreover, the GABA-activated tonic currents were enhanced by IFN-gamma. In conclusion, the potentiation of GABAergic currents in hippocampal neurons by IFN-gamma may contribute to the disturbed neuronal excitability and cognitive dysfunction during neuroinflammation.

Place, publisher, year, edition, pages
ELSEVIER, 2019
Keywords
gamma-Aminobutyric acid, Hippocampus, Interferon-gamma, Phasic inhibition, Tonic inhibition
National Category
Neurology
Identifiers
urn:nbn:se:uu:diva-400001 (URN)10.1016/j.jneuroim.2019.577050 (DOI)000498318800004 ()31505410 (PubMedID)
Funder
Swedish Research Council, Dnr 201502417Swedish Research Council, 2018-02952The Swedish Brain Foundation
Available from: 2019-12-19 Created: 2019-12-19 Last updated: 2019-12-19Bibliographically approved
Lam, M., Moslem, M., Bryois, J., Pronk, R. J., Uhlin, E., Ellström, I. D., . . . Falk, A. (2019). Single cell analysis of autism patient with bi-allelic NRXN1-alpha deletion reveals skewed fate choice in neural progenitors and impaired neuronal functionality. Experimental Cell Research, 383(1), Article ID UNSP 111469.
Open this publication in new window or tab >>Single cell analysis of autism patient with bi-allelic NRXN1-alpha deletion reveals skewed fate choice in neural progenitors and impaired neuronal functionality
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2019 (English)In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 383, no 1, article id UNSP 111469Article in journal (Refereed) Published
Abstract [en]

We generated human iPS derived neural stem cells and differentiated cells from healthy control individuals and an individual with autism spectrum disorder carrying bi-allelic NRXN1-alpha deletion. We investigated the expression of NRXN1-alpha during neural induction and neural differentiation and observed a pivotal role for NRXN1-alpha during early neural induction and neuronal differentiation. Single cell RNA-seq pinpointed neural stem cells carrying NRXN1-alpha deletion shifting towards radial glia-like cell identity and revealed higher proportion of differentiated astroglia. Furthermore, neuronal cells carrying NRXN1-alpha deletion were identified as immature by single cell RNA-seq analysis, displayed significant depression in calcium signaling activity and presented impaired maturation action potential profile in neurons investigated with electrophysiology. Our observations propose NRXN1-alpha plays an important role for the efficient establishment of neural stem cells, in neuronal differentiation and in maturation of functional excitatory neuronal cells.

Keywords
Autism spectrum disorder, Neurexin, Neurexin-1 alpha, Induced pluripotent stem cell, Neural stem cell, Single cell RNA sequencing, Neural development, Disease modeling
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-395420 (URN)10.1016/j.yexcr.2019.06.014 (DOI)000486736600011 ()31302032 (PubMedID)
Funder
Swedish Foundation for Strategic Research , IB13-0074Swedish Research Council, 2015-02424Swedish Research Council, D0886501Swedish Research Council, 2017-03407
Available from: 2019-10-22 Created: 2019-10-22 Last updated: 2019-10-22Bibliographically approved
Schuster, J., Laan, L., Klar, J., Jin, Z., Huss, M., Korol, S., . . . Dahl, N. (2019). Transcriptomes of Dravet syndrome iPSC derived GABAergic cells reveal dysregulated pathways for chromatin remodeling and neurodevelopment. Neurobiology of Disease, 132, Article ID 104583.
Open this publication in new window or tab >>Transcriptomes of Dravet syndrome iPSC derived GABAergic cells reveal dysregulated pathways for chromatin remodeling and neurodevelopment
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2019 (English)In: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 132, article id 104583Article in journal (Refereed) Published
Abstract [en]

Dravet syndrome (DS) is an early onset refractory epilepsy typically caused by de novo heterozygous variants in SCN1A encoding the a-subunit of the neuronal sodium channel Na(v)1.1. The syndrome is characterized by age related progression of seizures, cognitive decline and movement disorders. We hypothesized that the distinct neurodevelopmental features in DS are caused by the disruption of molecular pathways in Na(v)1.1 haploinsufficient cells resulting in perturbed neural differentiation and maturation. Here, we established DS-patient and control induced pluripotent stem cell derived neural progenitor cells (iPSC NPC) and GABAergic interneuronal (iPSC GABA) cells. The DS-patient iPSC GABA cells showed a shift in sodium current activation and a perturbed response to induced oxidative stress. Transcriptome analysis revealed specific dysregulations of genes for chromatin structure, mitotic progression, neural plasticity and excitability in DS-patient iPSC NPCs and DS-patient iPSC GABA cells versus controls. The transcription factors FOXM1 and E2F1, positive regulators of the disrupted pathways for histone modification and cell cycle regulation, were markedly up-regulated in DS-iPSC GABA lines. Our study highlights transcriptional changes and disrupted pathways of chromatin remodeling in Na(v)1.1 haploinsufficient GABAergic cells, providing a molecular framework that overlaps with that of neurodevelopmental disorders and other epilepsies.

Place, publisher, year, edition, pages
ACADEMIC PRESS INC ELSEVIER SCIENCE, 2019
Keywords
Dravet syndrome, SCN1A, Na(v)1.1, iPSC, Neural differentiation, Neurodevelopment, Chromatin architecture
National Category
Neurosciences
Identifiers
urn:nbn:se:uu:diva-398427 (URN)10.1016/j.nbd.2019.104583 (DOI)000497252500015 ()31445158 (PubMedID)
Funder
Swedish Research Council, 2015-02424Swedish Research Council, 2015-02417Knut and Alice Wallenberg FoundationAstraZenecaThe Swedish Brain Foundation, FO2018-0100The Swedish Brain Foundation, FO2019-0210Science for Life Laboratory - a national resource center for high-throughput molecular bioscience
Note

De tre första författarna delar förstaförfattarskapet.

Available from: 2019-12-06 Created: 2019-12-06 Last updated: 2019-12-09Bibliographically approved
Bhandage, A., Jin, Z., Korol, S. V., Tafreshiha, A., Gohel, P., Hellgren, C., . . . Birnir, B. (2018). Expression of calcium release-activated and voltage-gated calcium channels genes in peripheral blood mononuclear cells is altered in pregnancy and in type 1 diabetes. PLoS ONE, 13(12), Article ID e0208981.
Open this publication in new window or tab >>Expression of calcium release-activated and voltage-gated calcium channels genes in peripheral blood mononuclear cells is altered in pregnancy and in type 1 diabetes
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2018 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 12, article id e0208981Article in journal (Refereed) Published
Abstract [en]

Calcium (Ca2+) is an important ion in physiology and is found both outside and inside cells. The intracellular concentration of Ca2+ is tightly regulated as it is an intracellular signal molecule and can affect a variety of cellular processes. In immune cells Ca2+ has been shown to regulate e.g. gene transcription, cytokine secretion, proliferation and migration. Ca2+ can enter the cytoplasm either from intracellular stores or from outside the cells when Ca2+ permeable ion channels in the plasma membrane open. The Ca2+ release-activated (CRAC) channel is the most prominent Ca2+ ion channel in the plasma membrane. It is formed by ORAI1-3 and the channel is opened by the endoplasmic reticulum Ca2+ sensor proteins stromal interaction molecules (STIM) 1 and 2. Another group of Ca-2(+) channels in the plasma membrane are the voltage-gated Ca2+ (Ca-V) channels. We examined if a change in immunological tolerance is accompanied by altered ORAI, STIM and Ca-V gene expression in peripheral blood mononuclear cells (PBMCs) in pregnant women and in type 1 diabetic individuals. Our results show that in pregnancy and type 1 diabetes ORAI1-3 are up-regulated whereas STIM1 and 2 are down-regulated in pregnancy but only STIM2 in type 1 diabetes. Expression of L-, P/Q-, R- and T-type voltage-gated Ca2+ channels was detected in the PBMCs where the Ca(V)2.3 gene was up-regulated in pregnancy and type 1 diabetes whereas the Ca(V)2.1 and Ca(V)3.2 genes were up-regulated only in pregnancy and the Ca(V)1.3 gene in type 1 diabetes. The results are consistent with that expression of ORAI, STIM and Ca-V genes correlate with a shift in immunological status of the individual in health, as during pregnancy, and in the autoimmune disease type 1 diabetes. Whether the changes are in general protective or in type 1 diabetes include some pathogenic components remains to be clarified.

National Category
Endocrinology and Diabetes Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-372929 (URN)10.1371/journal.pone.0208981 (DOI)000453247500057 ()30543678 (PubMedID)
Funder
Swedish Research CouncilEXODIAB - Excellence of Diabetes Research in SwedenSwedish Diabetes AssociationSwedish Child Diabetes FoundationErnfors Foundation
Available from: 2019-01-10 Created: 2019-01-10 Last updated: 2019-01-10Bibliographically approved
Korol, S. V., Jin, Z., Jin, Y., Bhandage, A. K., Tengholm, A., Gandasi, N. R., . . . Birnir, B. (2018). Functional Characterization of Native, High-Affinity GABAA Receptors in Human Pancreatic β Cells. EBioMedicine, 30
Open this publication in new window or tab >>Functional Characterization of Native, High-Affinity GABAA Receptors in Human Pancreatic β Cells
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2018 (English)In: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, Vol. 30Article in journal (Refereed) Published
Abstract [en]

In human pancreatic islets, the neurotransmitter γ-aminobutyric acid (GABA) is an extracellular signaling molecule synthesized by and released from the insulin-secreting β cells. The effective, physiological GABA concentration range within human islets is unknown. Here we use native GABAA receptors in human islet β cells as biological sensors and reveal that 100-1000nM GABA elicit the maximal opening frequency of the single-channels. In saturating GABA, the channels desensitized and stopped working. GABA modulated insulin exocytosis and glucose-stimulated insulin secretion. GABAA receptor currents were enhanced by the benzodiazepine diazepam, the anesthetic propofol and the incretin glucagon-like peptide-1 (GLP-1) but not affected by the hypnotic zolpidem. In type 2 diabetes (T2D) islets, single-channel analysis revealed higher GABA affinity of the receptors. The findings reveal unique GABAA receptors signaling in human islets β cells that is GABA concentration-dependent, differentially regulated by drugs, modulates insulin secretion and is altered in T2D.

Keywords
GABA, GABA(A) receptor, Pancreatic islet, Type 2 diabetes
National Category
Other Medical Sciences not elsewhere specified Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-348267 (URN)10.1016/j.ebiom.2018.03.014 (DOI)000430303000032 ()29606630 (PubMedID)
Funder
Swedish Research Council, 521-2009-4021EXODIAB - Excellence of Diabetes Research in SwedenSwedish Child Diabetes FoundationSwedish Diabetes AssociationNovo NordiskSwedish Society for Medical Research (SSMF)Swedish Research Council, 521-2012-1789Swedish Research Council, 2015-02417Swedish Research Council, 2017-00956Swedish Research Council, 2014-2575
Note

De 2 första författarna delar förstaförfattarskapet.

Available from: 2018-04-11 Created: 2018-04-11 Last updated: 2018-06-19Bibliographically approved
Bhandage, A. K., Jin, Z., Korol, S. V., Shen, Q., Pei, Y., Deng, Q., . . . Birnir, B. (2018). GABA Regulates Release of Inflammatory Cytokines From Peripheral Blood Mononuclear Cells and CD4+ T Cells and Is Immunosuppressive in Type 1 Diabetes. EBioMedicine, 30, 283-294
Open this publication in new window or tab >>GABA Regulates Release of Inflammatory Cytokines From Peripheral Blood Mononuclear Cells and CD4+ T Cells and Is Immunosuppressive in Type 1 Diabetes
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2018 (English)In: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, Vol. 30, p. 283-294Article in journal (Refereed) Published
Abstract [en]

The neurotransmitter γ-aminobutyric acid (GABA) is an extracellular signaling molecule in the brain and in pancreatic islets. Here, we demonstrate that GABA regulates cytokine secretion from human peripheral blood mononuclear cells (PBMCs) and CD4+ T cells. In anti-CD3 stimulated PBMCs, GABA (100nM) inhibited release of 47 cytokines in cells from patients with type 1 diabetes (T1D), but only 16 cytokines in cells from nondiabetic (ND) individuals. CD4+ T cells from ND individuals were grouped into responder or non-responder T cells according to effects of GABA (100nM, 500nM) on the cell proliferation. In the responder T cells, GABA decreased proliferation, and inhibited secretion of 37 cytokines in a concentration-dependent manner. In the non-responder T cells, GABA modulated release of 8 cytokines. GABA concentrations in plasma from T1D patients and ND individuals were correlated with 10 cytokines where 7 were increased in plasma of T1D patients. GABA inhibited secretion of 5 of these cytokines from both T1D PBMCs and ND responder T cells. The results identify GABA as a potent regulator of both Th1- and Th2-type cytokine secretion from human PBMCs and CD4+ T cells where GABA generally decreases the secretion.

Keywords
PBMCs, Immune cells, Proliferation, Cytokine, GABAA receptor, Diabetes, T1D, Autoimmune disease, T cell
National Category
Other Medical Sciences not elsewhere specified Endocrinology and Diabetes
Research subject
Biology; Physiology
Identifiers
urn:nbn:se:uu:diva-348232 (URN)10.1016/j.ebiom.2018.03.019 (DOI)000430303000033 ()
Funder
Swedish Research Council, 2015-02417Swedish Diabetes AssociationSwedish Child Diabetes FoundationEXODIAB - Excellence of Diabetes Research in Sweden
Available from: 2018-04-11 Created: 2018-04-11 Last updated: 2018-06-19Bibliographically approved
Korol, S. V., Tafreshiha, A., Bhandage, A. K., Birnir, B. & Jin, Z. (2018). Insulin enhances GABAA receptor-mediated inhibitory currents in rat central amygdala neurons. Neuroscience Letters, 671, 76-81
Open this publication in new window or tab >>Insulin enhances GABAA receptor-mediated inhibitory currents in rat central amygdala neurons
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2018 (English)In: Neuroscience Letters, ISSN 0304-3940, E-ISSN 1872-7972, Vol. 671, p. 76-81Article in journal (Refereed) Published
Abstract [en]

Insulin, a pancreatic hormone, can access the central nervous system, activate insulin receptors distributed in selective brain regions and affect various cellular functions such as neurotransmission. We have previously shown that physiologically relevant concentration of insulin potentiates the GABAA receptor-mediated tonic inhibition and reduces excitability of rat hippocampal CA1 neurons. The central nucleus of the amygdala (CeA) comprises heterogeneous neuronal populations that can respond to hormonal stimulus. Using quantitative PCR and immunofluorescent labeling, we report that the mRNA and protein of the insulin receptor are abundantly expressed in the rat CeA. The insulin receptor mRNA is also detected in the CeA from post-mortem human brain samples. Furthermore, our whole-cell patch-clamp recordings show that the application of insulin (5 and 50 nM) selectively enhances the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) in rat CeA neurons. Our findings reveal that GABAergic synaptic transmission is a target in the CeA for insulin receptor signaling that may underlie insulin modulation of emotion- and feeding-related behaviors.

Keywords
γ-aminobutyric acid, neural inhibition, amygdala, insulin
National Category
Other Biological Topics Biophysics
Research subject
Neuroscience
Identifiers
urn:nbn:se:uu:diva-341839 (URN)10.1016/j.neulet.2018.02.022 (DOI)000430523700015 ()29447952 (PubMedID)
Funder
Swedish Research Council, Dnr 2015- 02417The Swedish Brain FoundationÅke Wiberg Foundation, 71959661, M14-0142
Available from: 2018-02-15 Created: 2018-02-15 Last updated: 2018-06-26Bibliographically approved
Bhandage, A. K., Jin, Z., Hellgren, C., Korol, S. V., Nowak, K., Williamsson, L., . . . Birnir, B. (2017). AMPA, NMDA and kainate glutamate receptor subunits are expressed in human peripheral blood mononuclear cells (PBMCs) where the expression of GluK4 is altered by pregnancy and GluN2D by depression in pregnant women. Journal of Neuroimmunology, 305, 51-58
Open this publication in new window or tab >>AMPA, NMDA and kainate glutamate receptor subunits are expressed in human peripheral blood mononuclear cells (PBMCs) where the expression of GluK4 is altered by pregnancy and GluN2D by depression in pregnant women
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2017 (English)In: Journal of Neuroimmunology, ISSN 0165-5728, E-ISSN 1872-8421, Vol. 305, p. 51-58Article in journal (Refereed) Published
Abstract [en]

The amino acid glutamate opens cation permeable ion channels, the iGlu receptors. These ion channels are abundantly expressed in the mammalian brain where glutamate is the main excitatory neurotransmitter. The neurotransmitters and their receptors are being increasingly detected in the cells of immune system. Here we examined the expression of the 18 known subunits of the iGlu receptors families; alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate, N-methyl-D-aspartate (NMDA) and delta in human peripheral blood mononuclear cells (PBMCs). We compared the expression of the subunits between four groups: men, non-pregnant women, healthy pregnant women and depressed pregnant women.

Out of 18 subunits of the iGlu receptors, mRNAs for 11 subunits were detected in PBMCs from men and nonpregnant women; AMPA: GluA3, GluA4, kainate: GluK2, GluK4, GluK5, NMDA: GluN1, GluN2C, GluN2D, GluN3A, GluN3B, and delta: GluD1. In the healthy and the depressed pregnant women, in addition, the delta GluD2 subunit was identified. The mRNAs for GluK4, GluK5, GluN2C and GluN2D were expressed at a higher level than other subunits. Gender, pregnancy or depression during pregnancy altered the expression of GluA3, GluK4, GluN2D, GluN3B and GluD1 iGlu subunit mRNAs. The greatest changes recorded were the lower GluA3 and GluK4 mRNA levels in pregnant women and the higher GluN2D mRNA level in healthy but not in depressed pregnant women as compared to non-pregnant individuals. Using subunit specific antibodies, the GluK4, GluK5, GluNl, GluN2C and GluN2D subunit proteins were identified in the PBMCs. The results show expression of specific iGlu receptor subunit in the PBMCs and support the idea of physiology-driven changes of iGlu receptors subtypes in the immune cells.

Keywords
Glutamate, iGluR subunits, Immune cells, Pregnancy, Depression, Physiology-driven changes
National Category
Medical and Health Sciences Neurosciences
Identifiers
urn:nbn:se:uu:diva-282410 (URN)10.1016/j.jneuroim.2017.01.013 (DOI)000397694200009 ()28284346 (PubMedID)
Funder
Swedish Research Council, 521-2012-1789
Available from: 2016-04-05 Created: 2016-04-05 Last updated: 2018-01-10Bibliographically approved
Babateen, O., Korol, S. V., Jin, Z., Bhandage, A. K., Ahemaiti, A. & Birnir, B. (2017). Liraglutide modulates GABAergic signaling in rat hippocampal CA3 pyramidal neurons predominantly by presynaptic mechanism. BMC Pharmacology & Toxicology, 18, Article ID 83.
Open this publication in new window or tab >>Liraglutide modulates GABAergic signaling in rat hippocampal CA3 pyramidal neurons predominantly by presynaptic mechanism
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2017 (English)In: BMC Pharmacology & Toxicology, E-ISSN 2050-6511, Vol. 18, article id 83Article in journal (Refereed) Published
Abstract [en]

Background

γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain where it regulates activity of neuronal networks. The receptor for glucagon-like peptide-1 (GLP-1) is expressed in the hippocampus, which is the center for memory and learning. In this study we examined effects of liraglutide, a GLP-1 analog, on GABA signaling in CA3 hippocampal pyramidal neurons.

Methods

We used patch-clamp electrophysiology to record synaptic and tonic GABA-activated currents in CA3 pyramidal neurons in rat hippocampal brain slices.

Results

We examined the effects of liraglutide on the neurons at concentrations ranging from one nM to one μM. Significant changes of the spontaneous inhibitory postsynaptic currents (sIPSCs) were only recorded with 100 nM liraglutide and then in just ≈50% of the neurons tested at this concentration. In neurons affected by liraglutide both the sIPSC frequency and the most probable amplitudes increased. When the action potential firing was inhibited by tetrodotoxin (TTX) the frequency and amplitude of IPSCs in TTX and in TTX plus 100 nM liraglutide were similar.

Conclusions

The results demonstrate that liraglutide regulation of GABA signaling of CA3 pyramidal neurons is predominantly presynaptic and more limited than has been observed for GLP-1 and exendin-4 in hippocampal neurons.

Keywords
GABA, GLP-1 receptor, patch-clamp, inhibitory postsynaptic and tonic currents, hippocampus, electrophysiology
National Category
Other Biological Topics Neurosciences Pharmacology and Toxicology
Research subject
Neuroscience; Pharmacology; Biology with specialization in Molecular Biology
Identifiers
urn:nbn:se:uu:diva-282424 (URN)10.1186/s40360-017-0191-0 (DOI)000418264400001 ()29246184 (PubMedID)
Projects
Effect of metabolic hormones on GABA signalling in the hippocampus
Funder
Swedish Research CouncilThe Swedish Brain FoundationEXODIAB - Excellence of Diabetes Research in SwedenÅke Wiberg Foundation
Available from: 2016-04-05 Created: 2016-04-05 Last updated: 2018-02-16Bibliographically approved
Fellerhoff-Losch, B., Korol, S. V., Ganor, Y., Gu, S., Cooper, I., Eilam, R., . . . Levite, M. (2016). Normal human CD4+ helper T cells express Kv1.1 voltage-gated K+ channels, and selective Kv1.1 block in T cells induces by itself robust TNFα production and secretion and activation of the NFκB non-canonical pathway. Journal of neural transmission, 123(3), 137-157
Open this publication in new window or tab >>Normal human CD4+ helper T cells express Kv1.1 voltage-gated K+ channels, and selective Kv1.1 block in T cells induces by itself robust TNFα production and secretion and activation of the NFκB non-canonical pathway
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2016 (English)In: Journal of neural transmission, ISSN 0300-9564, E-ISSN 1435-1463, Vol. 123, no 3, p. 137-157Article in journal (Refereed) Published
Abstract [en]

TNFα is a very potent and pleiotropic pro-inflammatory cytokine, essential to the immune system for eradicating cancer and microorganisms, and to the nervous system, for brain development and ongoing function. Yet, excess and/or chronic TNFα secretion causes massive tissue damage in autoimmune, inflammatory and neurological diseases and injuries. Therefore, many patients with autoimmune/inflammatory diseases receive anti-TNFα medications. TNFα is secreted primarily by CD4+ T cells, macrophages, monocytes, neutrophils and NK cells, mainly after immune stimulation. Yet, the cause for the pathologically high and chronic TNFα secretion is unknown. Can blocking of a particular ion channel in T cells induce by itself TNFα secretion? Such phenomenon was never revealed or even hypothesized. In this interdisciplinary study we discovered that: (1) normal human T cells express Kv1.1 voltage-gated potassium channel mRNA, and the Kv1.1 membrane-anchored protein channel; (2) Kv1.1 is expressed in most CD4+CD3+ helper T cells (mean CD4+CD3+Kv1.1+ T cells of 7 healthy subjects: 53.09 ± 22.17 %), but not in CD8+CD3+ cytotoxic T cells (mean CD8+CD3+Kv1.1+ T cells: 4.12 ± 3.04 %); (3) electrophysiological whole-cell recordings in normal human T cells revealed Kv currents; (4) Dendrotoxin-K (DTX-K), a highly selective Kv1.1 blocker derived from snake toxin, increases the rate of rise and decay of Kv currents in both resting and activated T cells, without affecting the peak current; (5) DTX-K by itself induces robust TNFα production and secretion by normal human T cells, without elevating IFNγ, IL-4 and IL-10; (6) intact Ca2+ channels are required for DTX-induced TNFα secretion; (7) selective anti-Kv1.1 antibodies also induce by themselves TNFα secretion; (8) DTX-K activates NFκB in normal human T cells via the unique non-canonical-pathway; (9) injection of Kv1.1-blocked human T cells to SCID mice, causes recruitment of resident mouse cells into the liver, alike reported after TNFα injection into the brain. Based on our discoveries we speculate that abnormally blocked Kv1.1 in T cells (and other immune cells?), due to either anti-Kv1.1 autoimmune antibodies, or Kv1.1-blocking toxins alike DTX-K, or Kv1.1-blocking genetic mutations, may be responsible for the chronic/excessive TNFα in autoimmune/inflammatory diseases. Independently, we also hypothesize that selective block of Kv1.1 in CD4+ T cells of patients with cancer or chronic infectious diseases could be therapeutic, since it may: a. augment beneficial secretion and delivery of TNFα to the disease-affected sites; b. induce recruitment and extravasation of curative immune cells and factors; c. improve accessibility of drugs to the brain and few peripheral organs thanks to TNFα-induced increased permeability of organ’s barriers.

Keywords
Autoimmune diseases, Immunotherapy, Inflammation, Kv1.1, NFκB, Non-canonical pathway, Pro-inflammatory cytokines, T cells, TNFα, Voltage-gated potassium channels
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-268200 (URN)10.1007/s00702-015-1446-9 (DOI)000373162900001 ()26611796 (PubMedID)
Available from: 2015-12-02 Created: 2015-12-02 Last updated: 2017-12-01Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-8279-2790

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