ORCID Profile
0000-0002-1763-0266
Current Organisations
Uppsala Universitet Medicinska fakulteten
,
Uppsala University
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Publisher: Wiley
Date: 08-03-2006
Publisher: Springer Science and Business Media LLC
Date: 12-1987
DOI: 10.1007/BF02209153
Publisher: Elsevier BV
Date: 04-2017
DOI: 10.1016/J.JNEUROIM.2017.01.013
Abstract: 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 α-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 non-pregnant 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 in iduals. Using subunit specific antibodies, the GluK4, GluK5, GluN1, 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.
Publisher: Elsevier BV
Date: 02-2017
DOI: 10.1016/J.NEUROSCIENCE.2016.07.018
Abstract: In the vertebrate brain, inhibition is largely mediated by γ-aminobutyric acid (GABA). This neurotransmitter comprises a signaling machinery of GABA
Publisher: Frontiers Media SA
Date: 05-12-2014
Publisher: Springer Science and Business Media LLC
Date: 12-2017
Publisher: Springer Science and Business Media LLC
Date: 27-04-2012
Publisher: Elsevier BV
Date: 05-2004
Publisher: Wiley
Date: 10-2000
Publisher: Public Library of Science (PLoS)
Date: 30-04-2015
Publisher: Springer Science and Business Media LLC
Date: 23-04-2006
DOI: 10.1038/NM1402
Abstract: Neurons have been neglected as cells with a major immune-regulatory function because they do not express major histocompatibility complex class II. Our data show that neurons are highly immune regulatory, having a crucial role in governing T-cell response and central nervous system (CNS) inflammation. Neurons induce the proliferation of activated CD4+ T cells through B7-CD28 and transforming growth factor (TGF)-beta1-TGF-beta receptor signaling pathways, resulting in lification of T-cell receptor signaling through phosphorylated ZAP-70, interleukin (IL)-2 and IL-9. The interaction between neurons and T cells results in the conversion of encephalitogenic T cells to CD25+ TGF-beta1+ CTLA-4+ FoxP3+ T regulatory (Treg) cells that suppress encephalitogenic T cells and inhibit experimental autoimmune encephalomyelitis. Suppression is dependent on cytotoxic T lymphocyte antigen (CTLA)-4 but not TGF-beta1. Autocrine action of TGF-beta1, however, is important for the proliferative arrest of Treg cells. Blocking the B7 and TGF-beta pathways prevents the CNS-specific generation of Treg cells. These findings show that generation of neuron-dependent Treg cells in the CNS is instrumental in regulating CNS inflammation.
Publisher: BMJ
Date: 10-2021
DOI: 10.1136/BMJDRC-2021-002442
Abstract: Experimentally, gamma-aminobutyric acid (GABA) has been found to exert immune-modulatory effects and induce beta-cell regeneration, which make it a highly interesting substance candidate for the treatment of type 1 diabetes (T1D). In many countries, including those in the European Union, GABA is considered a pharmaceutical drug. We have therefore conducted a safety and dose escalation trial with the first controlled-release formulation of GABA, Remygen (Diamyd Medical). Six adult male subjects with long-standing T1D (age 24.8±1.5 years, disease duration 14.7±2.2 years) were enrolled in an 11-day dose escalation trial with a controlled-release formulation of GABA, Remygen. Pharmacokinetics, glucose control and hormonal counter-regulatory response during hypoglycemic cl s were evaluated at every dose increase (200 mg, 600 mg and 1200 mg). During the trial there were no serious and only a few, transient, adverse events reported. Without treatment, the counter-regulatory hormone response to hypoglycemia was severely blunted. Intake of 600 mg GABA more than doubled the glucagon, epinephrine, growth hormone and cortisol responses to hypoglycemia. We find that the GABA treatment was well tolerated and established a counter-regulatory response to hypoglycemia in long-standing T1D. Further studies regarding not only the clinical potential of Remygen for beta-cell regeneration but also its potential use as hypoglycemic prophylaxis are warranted. NCT03635437 and EudraCT2018-001115-73.
Publisher: Frontiers Media SA
Date: 2014
Publisher: Wiley
Date: 03-2015
DOI: 10.1111/APHA.12467
Abstract: The GABAergic system is the main inhibitory neurotransmitter system in the central nervous system (CNS) of vertebrates. Signalling of the transmitter γ-aminobutyric acid (GABA) via GABA type A receptor channels or G-protein-coupled type B receptors is implicated in multiple CNS functions. Recent findings have implicated the GABAergic system in immune cell functions, inflammatory conditions and diseases in peripheral tissues. Interestingly, the specific effects may vary between immune cell types, with stage of activation and be altered by infectious agents. GABA/GABA-A receptor-mediated immunomodulatory functions have been unveiled in immune cells, being present in T lymphocytes and regulating the migration of Toxoplasma-infected dendritic cells. The GABAergic system may also play a role in the regulation of brain resident immune cells, the microglial cells. Activation of microglia appears to regulate the function of GABAergic neurotransmission in neighbouring neurones through changes induced by secretion of brain-derived neurotrophic factor. The neurotransmitter-driven immunomodulation is a new but rapidly growing field of science. Herein, we review the present knowledge of the GABA signalling in immune cells of the periphery and the CNS and raise questions for future research.
Publisher: Elsevier BV
Date: 03-2022
Publisher: Springer Science and Business Media LLC
Date: 11-1995
DOI: 10.1007/BF00207275
Abstract: Professional identity formation (PIF) in medical students is a multifactorial phenomenon, shaped by ways that clinical and non-clinical experiences, expectations and environmental factors merge with in idual values, beliefs and obligations. The relationship between students' evolving professional identity and self-identity or personhood remains ill-defined, making it challenging for medical schools to support PIF systematically and strategically. Primarily, to capture prevailing literature on PIF in medical school education, and secondarily, to ascertain how PIF influences on medical students may be viewed through the lens of the ring theory of personhood (RToP) and to identify ways that medical schools support PIF. A systematic scoping review was conducted using the systematic evidence-based approach. Articles published between 1 January 2000 and 1 July 2020 related to PIF in medical students were searched using PubMed, Embase, PsycINFO, ERIC and Scopus. Articles of all study designs (quantitative and qualitative), published or translated into English, were included. Concurrent thematic and directed content analyses were used to evaluate the data. A total of 10443 abstracts were identified, 272 full-text articles evaluated, and 76 articles included. Thematic and directed content analyses revealed similar themes and categories as follows: characteristics of PIF in relation to professionalism, role of socialization in PIF, PIF enablers and barriers, and medical school approaches to supporting PIF. PIF involves iterative construction, deconstruction and inculcation of professional beliefs, values and behaviours into a pre-existent identity. Through the lens of RToP, factors were elucidated that promote or hinder students' identity development on in idual, relational or societal levels. If inadequately or inappropriately supported, enabling factors become barriers to PIF. Medical schools employ an all-encompassing approach to support PIF, illuminating the need for distinct and deliberate longitudinal monitoring and mentoring to foster students' balanced integration of personal and professional identities over time.
Publisher: Springer Science and Business Media LLC
Date: 03-2000
Abstract: Spontaneous, single channel, chloride currents were recorded in 48% of cell-attached patches on neurones in the CA1 region of rat hippoc al slices. In some patches, there was more than 1 channel active. They showed outward rectification: both channel conductance and open probability were greater at depolarized than at hyperpolarized potentials. Channels activated by gamma-aminobutyric acid (GABA) in silent patches on the same neurones had similar conductance and outward rectification. The spontaneous currents were inhibited by bicuculline and potentiated by diazepam. It was concluded that the spontaneously opening channels were constitutively active, nonsynaptic GABA(A) channels. Such spontaneously opening GABA(A) channels may provide a tonic inhibitory mechanism in these cells and perhaps in other cells that have GABA(A) receptors although not having a GABA(A) synaptic input. They may also be a target for clinically useful drugs such as the benzodiazepines.
Publisher: Bioscientifica
Date: 10-2014
DOI: 10.1530/JOE-14-0531
Abstract: The Src homology-2 domain containing protein B (SHB) has previously been shown to function as a pleiotropic adapter protein, conveying signals from receptor tyrosine kinases to intracellular signaling intermediates. The overexpression of Shb in β-cells promotes β-cell proliferation by increased insulin receptor substrate (IRS) and focal adhesion kinase (FAK) activity, whereas Shb deficiency causes moderate glucose intolerance and impaired first-peak insulin secretion. Using an array of techniques, including live-cell imaging, patch-cl ing, immunoblotting, and semi-quantitative PCR, we presently investigated the causes of the abnormal insulin secretory characteristics in Shb -knockout mice. Shb -knockout islets displayed an abnormal signaling signature with increased activities of FAK, IRS, and AKT. β-catenin protein expression was elevated and it showed increased nuclear localization. However, there were no major alterations in the gene expression of various proteins involved in the β-cell secretory machinery. Nor was Shb deficiency associated with changes in glucose-induced ATP generation or cytoplasmic Ca 2 + handling. In contrast, the glucose-induced rise in cAMP, known to be important for the insulin secretory response, was delayed in the Shb -knockout compared with WT control. Inhibition of FAK increased the submembrane cAMP concentration, implicating FAK activity in the regulation of insulin exocytosis. In conclusion, Shb deficiency causes a chronic increase in β-cell FAK activity that perturbs the normal insulin secretory characteristics of β-cells, suggesting multi-faceted effects of FAK on insulin secretion depending on the mechanism of FAK activation.
Publisher: Frontiers Media SA
Date: 2012
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.NBD.2019.104583
Abstract: Dravet syndrome (DS) is an early onset refractory epilepsy typically caused by de novo heterozygous variants in SCN1A encoding the α-subunit of the neuronal sodium channel Na
Publisher: Wiley
Date: 10-06-2005
DOI: 10.1111/J.1471-4159.2005.03240.X
Abstract: We examined the interaction of GABA and the competitive inhibitor SR95531 at human α 1 β 1 γ 2S and α 1 β 1 GABA A receptors expressed in Sf 9 cells. The efficacy and potency of inhibition depended on the relative timing of the GABA and SR95531 applications. In saturating (10 m m ) GABA, the half‐inhibitory concentrations of SR95531 (IC 50 ) when coapplied with GABA to α 1 β 1 γ 2S or α 1 β 1 receptors were 49 and 210 µ m for the peak and 18 and 130 µ m for the plateau current, respectively. Our data are explained by an inhibition mechanism in which SR95531 and GABA bind to two sites on the receptor where the binding of GABA allows channel opening but SR95531 does not. The SR95531 affinity for both receptor types was ∼200 n m and the binding rate was found to be 10‐fold faster than that for GABA. The dual binding‐site model gives insights into the differential effects of GABA and SR95531 on the peak and plateau currents. The model predicts the effect of SR95531 on GABA currents in the synapse (GABA concentration ∼ m m ) and at extrasynaptic (GABA concentration ≤ µ m ) sites. The IC 50 (50–100 n m ) for the synaptic response to SR95531 was insensitive to the GABA affinity of the receptors whereas the IC 50 (50–800 n m ) for extrasynaptic inhibition correlated with the GABA affinity.
Publisher: Elsevier BV
Date: 1990
DOI: 10.1016/0167-4781(90)90028-Z
Abstract: Cells derived from the simian kidney, COS-7 cells, were transfected with a eucaryotic expression vector (pEUK-C1) containing the clone for the rabbit intestinal Na+/glucose cotransporter. Expression was monitored after transfection with lipofectin by measuring the initial rate of alpha-methylglucopyranoside (MeGlc) uptake. Cells transfected with vector containing the cDNA for the Na+/glucose cotransporter expressed Na(+)-dependent MeGlc transport. Neither control cells nor cells transfected with vector lacking cloned cDNA expressed the cotransporter. Na(+)-dependent MeGlc uptake into transfected cells was saturable (Km 150 microM), phlorizin-sensitive (Ki 11 microM), and inhibited by sugar analogs (D-glucose greater than MeGlc greater than D-galactose greater than 3-O-methyl-D-glucoside greater than D-allose much greater than L-glucose). Europium was able to mimic Na+ in driving MeGIC uptake. Finally, tunicamycin, an inhibitor of asparagine-linked glycosylation, inhibited the expression of Na(+)-dependent MeGlc transport 80%. We conclude that the rabbit intestinal Na+/glucose cotransporter expressed in COS-7 cell exhibits very similar kinetic properties to that in the native brush border and to that expressed in Xenopus oocytes. In addition, N-linked glycosylation appears to be important for functional expression of this membrane protein.
Publisher: Public Library of Science (PLoS)
Date: 06-12-2012
Publisher: Elsevier BV
Date: 09-2009
Publisher: Elsevier BV
Date: 08-2004
Publisher: Springer Science and Business Media LLC
Date: 13-12-2011
Publisher: American Diabetes Association
Date: 11-08-2014
DOI: 10.2337/DB14-0668
Abstract: Glucagon-like peptide-1 (GLP-1) is a hormone that stimulates insulin secretion. Receptors for GLP-1 are also found in the brain, including the hippoc us, the center for memory and learning. Diabetes is a risk factor for decreased memory functions. We studied effects of GLP-1 and exendin-4, a GLP-1 receptor agonist, on γ-aminobutyric acid (GABA) signaling in hippoc al CA3 pyramidal neurons. GABA is the main inhibitory neurotransmitter and decreases neuronal excitability. GLP-1 (0.01–1 nmol/L) transiently enhanced synaptic and tonic currents, and the effects were blocked by exendin (9-39). Ten pmol/L GLP-1 increased both the spontaneous inhibitory postsynaptic current (sIPSC) litudes and frequency by a factor of 1.8. In 0.1, 1 nmol/L GLP-1 or 10, 50, or 100 nmol/L exendin-4, only the sIPSC frequency increased. The tonic current was enhanced by 0.01–1 nmol/L GLP-1 and by 0.5–100 nmol/L exendin-4. When action potentials were inhibited by tetrodotoxin (TTX), inhibitory postsynaptic currents decreased and currents were no longer potentiated by GLP-1 or exendin-4. In contrast, although the tonic current decreased in TTX, it was still enhanced by GLP-1 or exendin-4. The results demonstrate GLP-1 receptor regulation of hippoc al function and are consistent with GLP-1 receptor agonists enhancing GABAA signaling by pre- and postsynaptic mechanisms.
Publisher: MyJove Corporation
Date: 17-07-2011
DOI: 10.3791/2858
Publisher: Frontiers Media SA
Date: 16-09-2014
Publisher: American Diabetes Association
Date: 04-2004
DOI: 10.2337/DIABETES.53.4.1038
Abstract: γ-Aminobutyric acid (GABA) has been proposed to function as a paracrine signaling molecule in islets of Langerhans. We have shown that rat β-cells release GABA by Ca2+-dependent exocytosis of synaptic-like microvesicles. Here we demonstrate that GABA thus released can diffuse over sufficient distances within the islet interstitium to activate GABAA receptors in neighboring cells. Confocal immunocytochemistry revealed the presence of GABAA receptors in glucagon-secreting α-cells but not in β- and δ-cells. RT-PCR analysis detected transcripts of α1 and α4 as well as β1–3 GABAA receptor subunits in purified α-cells but not in β-cells. In whole-cell voltage-cl recordings, exogenous application of GABA activated Cl− currents in α-cells. The GABAA receptor antagonist SR95531 was used to investigate the effects of endogenous GABA (released from β-cells) on pancreatic islet hormone secretion. The antagonist increased glucagon secretion at 1 mmol/l glucose twofold and completely abolished the inhibitory action of 20 mmol/l glucose on glucagon release. Basal and glucose-stimulated secretion of insulin and somatostatin were unaffected by SR95531. The L-type Ca2+ channel blocker isradipine evoked a paradoxical stimulation of glucagon secretion. This effect was not observed in the presence of SR95531, and we therefore conclude that isradipine stimulates glucagon secretion by inhibition of GABA release.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 09-2000
DOI: 10.1124/MOL.58.3.463
Publisher: Public Library of Science (PLoS)
Date: 17-05-2012
Publisher: Wiley
Date: 19-06-2019
DOI: 10.1111/APHA.13321
Publisher: Springer Science and Business Media LLC
Date: 03-1991
DOI: 10.1007/BF00370455
Abstract: A detailed histological study of pancreatic involution after ligation of the pancreatic duct is reported. Cytological evidence acinar cell damage is evident from the beginning and loss of zymogen granules occurs early. The acini diminish in size rapidly from the 36th hour to the 3rd day. The cell deletion appears to occur in 2 phases with apparently different characteristics. The first phase appears to be related to the initial cell damage. The letter phase is more general but of uncertain nature. Considerable proliferation of cells occurs in the ducts resulting, with the few remaining acinar cells, in duct-like structures which themselves undergo involution. The duct changes therefore are not passive but involve continued cell proliferation and cell death over a long period.
Publisher: Elsevier BV
Date: 04-2021
Publisher: Public Library of Science (PLoS)
Date: 09-05-2012
Publisher: Elsevier BV
Date: 04-1999
DOI: 10.1016/S0014-2999(99)00138-7
Abstract: Although there is a high degree of homology in the M2 transmembrane segments of alpha1 and beta1 subunits, subunit-specific effects were observed in alpha1beta1 GABA(A) receptors expressed in Spodoptera frugipedra (Sf9) cells when the conserved 13' threonine residue in the M2 transmembrane region was mutated to alanine. When threonine 263 (13') was mutated to alanine in the beta1 subunit, high-affinity muscimol binding and the response to GABA were abolished. This did not occur when the threonine 263 (13') was mutated to alanine in the alpha1 subunit, but the rate of desensitisation increased and the effect of bicuculline, a competitive inhibitor, was reduced. The results show differential effects of subunits on receptor function and support a role for M2 in desensitisation.
Publisher: Elsevier BV
Date: 2011
DOI: 10.1016/J.MOLIMM.2010.08.005
Abstract: GABA (γ-aminobutyric acid), the main inhibitory neurotransmitter in the central nervous system is also present in the pancreatic islet β cells where it may function as a paracrine molecule and perhaps as an immunomodulator of lymphocytes infiltrating the pancreatic islet. We examined CD4(+) and CD8(+) T cells from diabetes prone (DR(lyp/lyp)) or resistant (DR(+/+)) congenic biobreeding (BB) rats for expression of GABA(A) channels. Our results show that BB rat CD4(+) and CD8(+) T cells express α1, α2, α3, α4, α6, β3, γ1, δ, ρ1 and ρ2 GABA(A) channel subunits. In CD8(+) T cells from DR(lyp/lyp) animals the subunits were significantly upregulated relative to expression levels in the CD8(+) T cells from DR(+/+) rats as well as from CD4(+) T cells from both DR(lyp/lyp) and DR(+/+) rats. Functional channels were formed in the T cells and physiological concentrations of GABA (100 nM) decreased T cell proliferation. Our results are consistent with the hypothesis that GABA in the islets of Langerhans may diminish inflammation by inhibition of activated T lymphocytes.
Publisher: Rockefeller University Press
Date: 09-02-2004
Abstract: We have explored whether γ-aminobutyric acid (GABA) is released by regulated exocytosis of GABA-containing synaptic-like microvesicles (SLMVs) in insulin-releasing rat pancreatic β-cells. To this end, β-cells were engineered to express GABAA-receptor Cl−-channels at high density using adenoviral infection. Electron microscopy indicated that the average diameter of the SLMVs is 90 nm, that every β-cell contains ∼3,500 such vesicles, and that insulin-containing large dense core vesicles exclude GABA. Quantal release of GABA, seen as rapidly activating and deactivating Cl−-currents, was observed during membrane depolarizations from −70 mV to voltages beyond −40 mV or when Ca2+ was dialysed into the cell interior. Depolarization-evoked GABA release was suppressed when Ca2+ entry was inhibited using Cd2+. Analysis of the kinetics of GABA release revealed that GABA-containing vesicles can be ided into a readily releasable pool and a reserve pool. Simultaneous measurements of GABA release and cell capacitance indicated that exocytosis of SLMVs contributes ∼1% of the capacitance signal. Mathematical analysis of the release events suggests that every SLMV contains 0.36 amol of GABA. We conclude that there are two parallel pathways of exocytosis in pancreatic β-cells and that release of GABA may accordingly be temporally and spatially separated from insulin secretion. This provides a basis for paracrine GABAergic signaling within the islet.
Publisher: Cold Spring Harbor Laboratory
Date: 12-05-2019
DOI: 10.1101/635144
Abstract: In pancreatic islets the major cell-types are α, β and δ cells, secreting the hormones glucagon (GCG), insulin (INS) and somatostatin (SST), respectively. The GABA (γ-aminobutyric acid) signalling system is expressed in human pancreatic islets. We have previously used single-cell RT-PCR in combination with current recordings to correlate expression of single hormone transcript with functional GABA A receptor ( iGABA A R ) properties in islets. Here we extended these studies to islet cells from non-diabetic and type 2 diabetic donors that express mRNAs for more than one hormone. We detected cells expressing double (α/β, α/δ, β/δ cell-types) and triple (α/β/δ cell-type) hormone transcripts. The most common mixed-identity cell-type was the α/β group where the cells could be grouped into β- and α-like subgroups. The β-like cells had low GCG/INS expression ratio ( 0.6) and significantly higher frequency of single-channel iGABA A R openings than the α-like cells where the GCG/INS expression ratio was high ( 1.2). The difference in expression levels and single channel iGABA A R characteristics varied in the α/β/δ cell-type. No correlation was observed between the cell-types identity with time in culture or cell size. Clearly, multiple hormone transcripts can be expressed in islet cells whereas iGABA A R functional properties appear α or β cell specific.
Publisher: Springer Science and Business Media LLC
Date: 06-2001
DOI: 10.1007/S00232-001-0021-5
Abstract: GABAA channels were activated by GABA in outside-out patches from rat cultured hippoc al neurons. They were blocked by bicuculline and potentiated by diazepam. In 109 of 190 outside-out patches, no channels were active before exposure to GABA (silent patches). The other 81 patches showed spontaneous channel activity. In patches containing spontaneous channel activity, rapid application of GABA rapidly activated channels. In 93 of the silent patches, channels could be activated by GABA but only after a delay that was sometimes as long as 10 minutes. The maximum channel conductance of the channels activated after a delay increased with GABA concentration from less than 10 pS (0.5 microm GABA) to more than 100 pS (10 mm GABA). Fitting the data with a Hill-type equation gave an EC50 value of 33 microm and a Hill coefficient of 0.6. The channels showed outward rectification and were chloride selective. In the presence of 1 microm diazepam, the GABA EC50 decreased to 0.2 microm but the maximum conductance was unchanged. Diazepam decreased the average latency for channel opening. Bicuculline, a GABA antagonist, caused a concentration-dependent decrease in channel conductance. In channels activated with 100 microm GABA the bicuculline IC50 was 19 microm. The effect of GABA on channel conductance shows that the role of the ligand in GABAA receptor channel function is more complex than previously thought.
Publisher: Elsevier BV
Date: 12-1999
DOI: 10.1016/S0014-2999(99)00710-4
Abstract: Pentobarbital activates GABA(A) receptors and enhances GABA-activated currents. A threonine residue (262) in the second membrane spanning region at the 12' position in the beta(1) subunit, alpha(1)beta(1)(T12'Q), is necessary for the potentiating action of pentobarbital. We examined whether T12'Q-mutated receptors expressed in Spodoptera frugipedra (Sf 9) cells responded to direct activation by pentobarbital. In both mutant and wild type receptors, pentobarbital (100 microM to 1 mM) evoked a current response. The pentobarbital EC(50) values were similar 119 and 158 microM for alpha(1)beta(1) and alpha(1)beta(1)(T12'Q) receptors, respectively. The results show it is possible to discriminate between agonistic and potentiating effects of pentobarbital, suggesting these actions involve separate mechanisms.
Publisher: Elsevier BV
Date: 09-2003
DOI: 10.1016/S1044-7431(03)00128-3
Abstract: Single-channel currents were activated by THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) in cell-attached patches on CA1 pyramidal neurons in the rat hippoc al slice preparation. THIP activated GABA(A) channels after a delay that was concentration-dependent and decreased by 1 microM diazepam. The currents showed outward rectification. Channels activated at depolarized 40 mV relative to the chloride reversal potential had low conductance ( 40 pS). The average maximal-channel conductances for 2 and 100 microM THIP were 59 and 62 pS (-Vp = 40 mV), respectively, whereas in 2 microM THIP plus 1 microM diazepam, it was 71 pS. The results show that in hippoc al neurons THIP activates channels with characteristics similar to those of channels activated by low concentrations (0.5-5 microM ) of GABA. The increase in the inhibitory conductance with membrane depolarization permits gradation of the shunt pathway relative to the level of the excitatory input.
Publisher: Wiley
Date: 07-1997
DOI: 10.1002/(SICI)1098-2396(199707)26:3<324::AID-SYN13>3.0.CO;2-V
Publisher: Springer Vienna
Date: 2012
Publisher: Elsevier BV
Date: 11-2022
Publisher: MDPI AG
Date: 31-12-2021
DOI: 10.3390/BIOMEDICINES10010091
Abstract: Gamma-aminobutyric acid (GABA) is an important inhibitory neurotransmitter in the central nervous system (CNS) and outside of the CNS, found in the highest concentrations in immune cells and pancreatic beta-cells. GABA is gaining increasing interest in diabetes research due to its immune-modulatory and beta-cell stimulatory effects and is a highly interesting drug candidate for the treatment of type 1 diabetes (T1D). GABA is synthesized from glutamate by glutamic acid decarboxylase (GAD), one of the targets for autoantibodies linked to T1D. Using mass spectrometry, we have quantified the endogenous circulating levels of GABA in patients with new-onset and long-standing T1D and found that the levels are unaltered when compared to healthy controls, i.e., T1D patients do not have a deficit of systemic GABA levels. In T1D, GABA levels were negatively correlated with IL-1 beta, IL-12, and IL-15 15 and positively correlated to levels of IL-36 beta and IL-37. Interestingly, GABA levels were also correlated to the levels of GAD-autoantibodies. The unaltered levels of GABA in T1D patients suggest that the GABA secretion from beta-cells only has a minor impact on the circulating systemic levels. However, the local levels of GABA could be altered within pancreatic islets in the presence of GAD-autoantibodies.
Publisher: MDPI AG
Date: 17-01-2020
DOI: 10.3390/IJMS21020600
Abstract: In pancreatic islets, the major cell-types are α, β and δ cells. The γ-aminobutyric acid (GABA) signalling system is expressed in human pancreatic islets. In single hormone transcript-expressing cells, we have previously characterized the functional properties of islet GABAA receptors (iGABAARs). Here, we extended these studies to islet cells expressing mRNAs for more than one hormone and sought for correlation between iGABAAR activity level and relative mRNA expression ratio. The single-cell RT-PCR in combination with the patch-cl current recordings was used to examine functional properties of iGABAARs in the multiple hormone mRNA-expressing cells. We detected cells expressing double (α/β, α/δ, β/δ cell-types) and triple (α/β/δ cell-type) hormone transcripts. The most common mixed-identity cell-type was the α/β group where the cells could be grouped into β- and α-like subgroups. The β-like cells had low GCG/INS expression ratio ( .6) and significantly higher frequency of iGABAAR single-channel openings than the α-like cells where the GCG/INS expression ratio was high ( .2). The hormone expression levels and iGABAAR single-channel characteristics varied in the α/β/δ cell-type. Clearly, multiple hormone transcripts can be expressed in islet cells whereas iGABAAR single-channel functional properties appear to be α or β cell specific.
Publisher: Public Library of Science (PLoS)
Date: 13-12-2018
Publisher: The Royal Society
Date: 22-12-1992
Abstract: The baculovirus expression system was used to produce alpha 1 and beta 1 subunits of the human GABAA receptor in Sf9 cells. In cells infected with both alpha 1 and beta 1 recombinant viruses, GABA elicited an outwardly rectifying chloride current that was blocked by bicuculline and potentiated by pentobarbitone. GABA did not produce detectable currents in cells infected with either alpha 1 or beta 1 recombinant viruses alone. In these cells, and in control (non-infected) Sf9 cells, pentobarbitone depressed the leakage current (Ki = 55 microM). Fluorescently labelled monoclonal antibodies to the alpha 1 subunit showed greater amounts of the alpha 1 subunit in cells infected with only the alpha 1 recombinant virus than in cells co-infected with the alpha 1 and beta 1 recombinant viruses. Fluorescence of the plasma membrane was seen in cells co-infected with the alpha 1 and beta 1 recombinant viruses, but was absent in cells infected with only the alpha 1 recombinant virus. It was concluded that the alpha 1 subunit normally interacts with the beta 1 subunit to be transported to the plasma membrane in Sf9 cells.
Publisher: Elsevier BV
Date: 04-2018
Publisher: Public Library of Science (PLoS)
Date: 21-08-2012
Publisher: Elsevier BV
Date: 02-2015
DOI: 10.1016/J.EJPHAR.2014.12.001
Abstract: GABAA receptors are pentameric chloride ion channels that are opened by GABA. We have screened a cell line derived from human glioblastoma, U3047MG, for expression of GABAA receptor subunit isoforms and formation of functional ion channels. We identified GABAA receptors subunit α2, α3, α5, β1, β2, β3, δ, γ3, π, and θ mRNAs in the U3047MG cell line. Whole-cell GABA-activated currents were recorded and the half-maximal concentration (EC₅₀) for the GABA-activated current was 36 μM. The currents were activated by THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) and enhanced by the benzodiazepine diazepam (1 μM) and the general anesthetics etomidate and propofol (50 μM). In line with the expressed GABAA receptors containing at least the α3β3θ subunits, the receptors were highly sensitive to etomidate (EC₅₀=55 nM). Immunocytochemistry identified expression of the α3 and β3 subunit proteins. Our results show that the GABAA receptors in the glial cell line are functional and are modulated by classical GABAA receptor drugs. We propose that the U3047MG cell line may be used as a model system to study GABAA receptors function and pharmacology in glial cells.
Publisher: Wiley
Date: 21-01-2015
DOI: 10.1111/APHA.12440
Abstract: The concept of nerve‐driven immunity recognizes a link between the nervous and the immune system. γ ‐aminobutyric acid ( GABA ) is the main inhibitory neurotransmitter in the brain, and receptors activated by GABA can be expressed by immune cells. Here, we examined whether the expression of GABA receptors and chloride transporters in human peripheral blood mononuclear cells ( PBMC s) was influenced by gender, pregnancy or mental health. We used RT ‐ qPCR to determine the mRNA expression level in PBMCs from men ( n = 16), non‐pregnant women ( n = 19), healthy pregnant women ( n = 27) and depressed pregnant women ( n = 15). The ρ 2 subunit had the most prominent expression level of the GABA ‐A receptor subunits in all s les. The δ and ρ 2 subunits were up‐regulated by pregnancy, whereas the ε subunit was more frequently expressed in healthy pregnant women than non‐pregnant women who, in turn, commonly expressed the α 6 and the γ 2 subunits. The β 1 and ε subunits expression was altered by depression in pregnant women. The GABA ‐B1 receptor was up‐regulated by depression in pregnant women, while the transporters NKCC 1 and KCC 4 were down‐regulated by pregnancy. The changes recorded in the mRNA expression levels imply participation of GABA receptors in establishing and maintaining tolerance in pregnancy. Importantly, the correlation of mental health with the expression of specific receptor subunits reveals a connection between the immune cells and the brain. Biomarkers for mental health may be identified in PBMC s. The results demonstrate the impact gender, pregnancy and mental health have on the expression of GABA receptors and chloride transporters expressed in human PBMC s.
Publisher: Wiley
Date: 10-2003
Publisher: Elsevier BV
Date: 04-2018
Publisher: Bentham Science Publishers Ltd.
Date: 11-2007
DOI: 10.2174/138161207782341330
Abstract: Most studies of GABA(A) receptor accessory proteins have focused on trafficking, clustering and phosphorylation state of the channel-forming subunits and as a result a number of proteins and mechanisms have been identified that can influence the GABA(A) channel expression and function in the cell plasma membrane. In the light of a growing list of intracellular and transmembrane neuronal proteins shown to affect the fate, function and pharmacology of the GABA(A) receptors in neurons, the concept of what constitutes the native GABA(A) receptor complex may need to be re-examined. It is perhaps more appropriate to consider the associated proteins or some of them to be parts of the receptor channel complex in the capacity of ancillary proteins. Here we highlight some of the effects the intracellular environment has on the GABA-activated channel function and pharmacology. The studies demonstrate the need for co-expression of accessory proteins with the GABA(A) channel-forming subunits in heterologous expression systems in order to obtain the full repertoire of GABA(A) receptors characteristics recorded in the native neuronal environment. Further studies e.g. on gene-modified animal models are needed for most of the accessory proteins to establish their significance in normal physiology and in pathophysiology of neurological and psychiatric diseases. The challenge remains to elucidate the effects that the accessory proteins and processes (e.g. phosphorylation) plus the sub-cellular location have on the "fine-tuning" of the functional and pharmacological properties of the GABA(A) receptor channels.
Publisher: Public Library of Science (PLoS)
Date: 24-06-2013
Publisher: Springer Science and Business Media LLC
Date: 10-1994
DOI: 10.1007/BF00233386
Publisher: Elsevier BV
Date: 05-2003
DOI: 10.1016/S0014-2999(03)01641-8
Abstract: Channels were activated, in ripped-off patches from rat-cultured hippoc al neurons, by propofol alone, propofol plus 0.5 microM GABA (gamma-aminobutyric acid) or GABA alone. The propofol-activated currents were chloride-selective, showed outward-rectification and were enhanced by 1 microM diazepam. The maximum propofol-activated channel conductance increased with propofol concentration from less than 15 pS (10 microM) to about 60 pS (500 microM) but decreased to 40 pS in 1 mM propofol. Fitting the data from 10 to 500 microM propofol with a Hill-type equation gave a maximum conductance of 64 pS, an EC50 value of 32 microM and a Hill coefficient of 1.1. Addition of 0.5 microM GABA shifted the propofol EC50 value to 10 microM and increased the maximum channel conductance to about 100 pS. The Hill coefficient was 0.8. The maximum channel conductance did not increase further when 1 microM diazepam was added together with a saturating propofol concentration and GABA. The results are compared to effects other drugs have on GABAA channels conductance.
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1016/J.NEULET.2018.02.022
Abstract: 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 GABA
Publisher: Springer Science and Business Media LLC
Date: 07-1997
DOI: 10.1038/40404
Abstract: Benzodiazepines, which are widely used clinically for relief of anxiety and for sedation, are thought to enhance synaptic inhibition in the central nervous system by increasing the open probability of chloride channels activated by the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Here we show that the benzodiazepine diazepam can also increase the conductance of GABAA channels activated by low concentrations of GABA (0.5 or 5 microM) in rat cultured hippoc al neurons. Before exposure to diazepam, chloride channels activated by GABA had conductances of 8 to 53pS. Diazepam caused a concentration-dependent and reversible increase in the conductance of these channels towards a maximum conductance of 70-80 pS and the effect was as great as 7-fold in channels of lowest initial conductance. Increasing the conductance of GABAA channels tonically activated by low ambient concentrations of GABA in the extracellular environment may be an important way in which these drugs depress excitation in the central nervous system. That any drug has such a large effect on single channel conductance has not been reported previously and has implications for models of channel structure and conductance.
Publisher: Elsevier BV
Date: 09-2003
DOI: 10.1016/J.EJPHAR.2003.08.034
Abstract: Gaboxadol (THIP 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) is an agonist at GABA(A) receptors. THIP concentrations (0.01-50 mM) were applied rapidly to Sf9 cells expressing the human alpha(1)beta(2)gamma(2S) GABA(A) receptors. The EC(50) values for the peak current in THIP alone or THIP plus 1 microM diazepam were 154 and 53 microM, respectively. In supersaturating THIP (10-50 mM) the rate of current decay increased and an off-current developed when THIP was rapidly removed. The mean currents measured over the first 4 s in 10 mM and higher THIP concentrations were 0.6 or less of the 1 mM THIP mean current. Diazepam (1 microM) increased the 4 s mean current when evoked by 10 to 20 mM THIP but not 50 mM THIP. No similar effects on the current time-course were recorded in supersaturating gamma-aminobutyric acid (GABA) concentrations (50 and 80 mM). The results demonstrate an inhibitory as well as agonist effect of THIP at alpha(1)beta(2)gamma(2S) GABA(A) receptors.
Publisher: Springer Science and Business Media LLC
Date: 15-01-1997
Abstract: Functional properties of the alpha1beta1 GABAA receptor changes in a subunit-specific manner when a threonine residue in the M2 region at the 12' position was mutated to glutamine. The rate and extent of desensitization increased in all mutants but the rate of activation was faster in the beta1 mutants. A negligible plateau current and abolition of potentiation by pentobarbitone of the GABA-activated current depended on the Thr 12' Gln mutation being present in the beta1 subunit. The Hill coefficient of the peak current response to GABA was reduced to less than one also in a beta1 subunit-specific manner. It was concluded that the beta1 subunit dominated conformational changes activated by GABA.
Publisher: Public Library of Science (PLoS)
Date: 02-12-2013
Publisher: Springer Science and Business Media LLC
Date: 11-1996
Abstract: The conserved leucine residues at the 9' positions in the M2 segments of alpha1 (L264) and beta1 (L259) subunits of the human GABAA receptor were replaced with threonine. Normal or mutant alpha1 subunits were co-expressed with normal or mutant beta1 subunits in Sf9 cells using the baculovirus/Sf9 expression system. Cells in which one or both subunits were mutated had a higher "resting" chloride conductance than cells expressing wild-type alpha1beta1 receptors. This chloride conductance was blocked by 10 mM penicillin, a recognized blocker of GABAA channels, but not by bicuculline (100 microm) or picrotoxin (100 microm) which normally inhibit the chloride current activated by GABA: nor was it potentiated by pentobarbitone (100 microM). In cells expressing wild-type beta1 with mutated alpha1 subunits, an additional chloride current could be elicited by GABA but the rise time and decay were slower than for wild-type alpha1beta1 receptors. In cells expressing mutated beta1 subunits with wild-type or mutated alpha1 subunits (alphabeta(L9'T) and alpha(L9'T)beta(L9'T)), no response to GABA could be elicited: this was not due to an absence of GABAA receptors in the plasmalemma because the cells bound [3H]-muscimol. It was concluded that in GABAA channels containing the L9'T mutation in the beta1 subunit, GABA-binding does not cause opening of channels, and that the L9'T mutation in either or both subunits gives an open-channel state of the GABAA receptor in the absence of ligand.
Publisher: MDPI AG
Date: 06-12-2019
DOI: 10.3390/IJMS20246172
Abstract: Immunomodulation is increasingly being recognised as a part of mental diseases. Here, we examined whether levels of immunological protein markers changed with depression, age, or the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). An analysis of plasma s les from patients with a major depressive episode and control blood donors (CBD) revealed the expression of 67 inflammatory markers. Thirteen of these markers displayed augmented levels in patients compared to CBD. Twenty-one markers correlated with the age of the patients, whereas 10 markers correlated with the age of CBD. Interestingly, CST5 and CDCP1 showed the strongest correlation with age in the patients and CBD, respectively. IL-18 was the only marker that correlated with the MADRS-S scores of the patients. Neuronal growth factors (NGFs) were significantly enhanced in plasma from the patients, as was the average plasma GABA concentration. GABA modulated the release of seven cytokines in anti-CD3-stimulated peripheral blood mononuclear cells (PBMCs) from the patients. The study reveals significant changes in the plasma composition of small molecules during depression and identifies potential peripheral biomarkers of the disease.
Publisher: Springer Science and Business Media LLC
Date: 12-1993
DOI: 10.1007/BF00233666
Publisher: Frontiers Media SA
Date: 24-09-2019
Publisher: Public Library of Science (PLoS)
Date: 14-01-2011
Publisher: Elsevier BV
Date: 06-2001
DOI: 10.1016/S0028-3908(01)00032-6
Abstract: We examined if the drug sensitivity of GABA(A) receptors in dentate gyrus granule neurons changed during the whole-cell current time-course. Effects of drugs on currents evoked immediately (the peak current) upon drug application and currents remaining about two seconds later (semi-plateau current) were compared. The apparent affinity for GABA (EC(50)) of the peak and the semi-plateau current were 14 and 4 microM, respectively. Bicuculline inhibited 50% of the peak and the semi-plateau current (IC(50)) at 7 and 36 microM, respectively, while 100 microM was required for full inhibition of the 100 microM GABA-evoked current. Zinc inhibited about 50% of the peak current with an IC(50) value of 94 microM whereas biphasic, but complete inhibition of the semi-plateau current was recorded with IC(50) values of 3 and 558 microM. The decay phase of the 100 microM GABA-evoked current was fitted by a fast (tau(1), 100-300 ms) and a slow (tau(2), 1-2 s) time-constants in all cells. The relative current litude associated with the fast (A1) and the slow (A2) component varied. The A1 current litude appeared more sensitive to bicuculline than the A2 current while the opposite was true for zinc. The results are consistent with heterogenous population of functional GABA(A) receptors in the dentate gyrus granule neurons.
Publisher: Elsevier BV
Date: 12-2008
DOI: 10.1016/J.JNEUROIM.2008.08.017
Abstract: gamma-aminobutyric acid (GABA) is the main neuroinhibitory transmitter in the brain. Here we show that GABA in the extracellular space may affect the fate of pathogenic T lymphocytes entering the brain. We examined in encephalitogenic T cells if they expressed functional GABA channels that could be activated by the low (nM-1 microM), physiological concentrations of GABA present around neurons in the brain. The cells expressed the alpha1, alpha4, beta2, beta3, gamma1 and delta GABAA channel subunits and formed functional, extrasynaptic-like GABA channels that were activated by 1 microM GABA. 100 nM and higher GABA concentrations decreased T cell proliferation. The results are consistent with GABA being immunomodulatory.
Publisher: Frontiers Media SA
Date: 24-10-2022
DOI: 10.3389/FNMOL.2022.988993
Abstract: Mowat-Wilson syndrome (MWS) is a severe neurodevelopmental disorder caused by heterozygous variants in the gene encoding transcription factor ZEB2 . Affected in iduals present with structural brain abnormalities, speech delay and epilepsy. In mice, conditional loss of Zeb2 causes hippoc al degeneration, altered migration and differentiation of GABAergic interneurons, a heterogeneous population of mainly inhibitory neurons of importance for maintaining normal excitability. To get insights into GABAergic development and function in MWS we investigated ZEB2 haploinsufficient induced pluripotent stem cells (iPSC) of MWS subjects together with iPSC of healthy donors. Analysis of RNA-sequencing data at two time points of GABAergic development revealed an attenuated interneuronal identity in MWS subject derived iPSC with enrichment of differentially expressed genes required for transcriptional regulation, cell fate transition and forebrain patterning. The ZEB2 haploinsufficient neural stem cells (NSCs) showed downregulation of genes required for ventral telencephalon specification, such as FOXG1, accompanied by an impaired migratory capacity. Further differentiation into GABAergic interneuronal cells uncovered upregulation of transcription factors promoting pallial and excitatory neurons whereas cortical markers were downregulated. The differentially expressed genes formed a neural protein-protein network with extensive connections to well-established epilepsy genes. Analysis of electrophysiological properties in ZEB2 haploinsufficient GABAergic cells revealed overt perturbations manifested as impaired firing of repeated action potentials. Our iPSC model of ZEB2 haploinsufficient GABAergic development thus uncovers a dysregulated gene network leading to immature interneurons with mixed identity and altered electrophysiological properties, suggesting mechanisms contributing to the neuropathogenesis and seizures in MWS.
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.JNEUROIM.2019.577050
Abstract: The neural transmission and plasticity can be differentially modulated by various elements of the immune system. Interferon-γ (IFN-γ) 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-γ on the γ-aminobutyric acid (GABA)-mediated currents in the hippoc us, a major brain region involved in the cognitive function, has not been investigated. Here we detected abundant expression of both IFN-γ receptor subunit gene transcripts (Ifngr1 and Ifngr2) in the rat hippoc us by quantitative PCR. In addition, we pre-incubated rat hippoc al slices with IFN-γ (100 ng/ml) and recorded GABA-activated spontaneous and miniature postsynaptic inhibitory currents (sIPSCs and mIPSCs) and tonic currents in hippoc al CA1 pyramidal neurons by the whole-cell patch-cl method. The pre-incubation with IFN-γ increased the frequency but not the mean litude, rise time or decay time of both sIPSCs and mIPSCs in hippoc al CA1 pyramidal neurons, suggesting a presynaptic effect of IFN-γ. Moreover, the GABA-activated tonic currents were enhanced by IFN-γ. In conclusion, the potentiation of GABAergic currents in hippoc al neurons by IFN-γ may contribute to the disturbed neuronal excitability and cognitive dysfunction during neuroinflammation.
Publisher: Elsevier BV
Date: 11-2005
Publisher: Elsevier BV
Date: 12-2003
DOI: 10.1016/J.NEULET.2003.09.025
Abstract: Granule neurons from the rat dentate gyrus were acutely isolated and whole-cell currents recorded. Maximal enhancement of 7 microM gamma-aminobutyric acid (GABA EC30) evoked currents was obtained with 100 microM pentobarbital where the peak-current was 2.1+/-0.2 of control. One hundred microM pentobarbital alone evoked no current response whereas 1 mM pentobarbital elicited a current response that was 0.4+/-0.2 of the 100 microM GABA-activated peak current. In 100 microM pentobarbital, the GABA EC50 value shifted from 14 to 3 microM but the peak-saturating-current value was not altered. An off-current was recorded on removal of 100 microM and higher pentobarbital concentrations. Ten mM pentobarbital abolished the peak-current response to 7 and 100 microM GABA. The results show that in the granule neurons the drug potency differs for the different effects of pentobarbital at GABAA receptors with the modulatory and inhibitory effects requiring lower concentrations than the direct activation of the receptors.
Publisher: Cold Spring Harbor Laboratory
Date: 02-07-2019
DOI: 10.1101/689984
Abstract: Immunomodulation is increasingly being recognised as a part of mental diseases. Here, we examined if levels of immunological protein markers altered with depression, age or by the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Analysis of plasma s les from patients with major depressive episode and control blood donors (CBD) revealed expression of 67 inflammatory markers. Thirteen of these markers had augmented levels in patients as compared to CBD. and 21 markers correlated with age of the patients, whereas 10 markers correlated with the age of CBD. Interestingly, CST5 and CDCP1 showed the strongest correlation with age in the patients and in the CBD, respectively. IL-18 was the only marker that correlated with the MADRS-S scores of the patients. Neuronal growth factors (NGFs) were significantly enhanced in plasma from the patients and so was the average plasma GABA concentration. GABA modulated release of seven cytokines in CD3 + stimulated peripheral blood mononuclear cells (PBMC) from the patients. The study reveals significant changes in plasma composition of small molecules during depression and identifies potential peripheral biomarkers of the disease.
Publisher: Wiley
Date: 21-03-2021
DOI: 10.1111/APHA.13623
Abstract: We examined if tonic γ‐aminobutyric acid (GABA)‐activated currents in primary hippoc al neurons were modulated by insulin in wild‐type and tg‐APPSwe mice, an Alzheimer's disease (AD) model. GABA‐activated currents were recorded in dentate gyrus (DG) granule cells and CA3 pyramidal neurons in hippoc al brain slices, from 8 to 10 weeks old (young) wild‐type mice and in dorsal DG granule cells in adult, 5‐6 and 10‐12 (aged) months old wild‐type and tg‐APPSwe mice, in the absence or presence of insulin, by whole‐cell patch‐cl electrophysiology. In young mice, insulin (1 nmol/L) enhanced the total spontaneous inhibitory postsynaptic current (sIPSC T ) density in both dorsal and ventral DG granule cells. The extrasynaptic current density was only increased by insulin in dorsal CA3 pyramidal neurons. In absence of action potentials, insulin enhanced DG granule cells and dorsal CA3 pyramidal neurons miniature IPSC (mIPSC) frequency, consistent with insulin regulation of presynaptic GABA release. sIPSC T densities in DG granule cells were similar in wild‐type and tg‐APPSwe mice at 5‐6 months but significantly decreased in aged tg‐APPSwe mice where insulin normalized currents to wild‐type levels. The extrasynaptic current density was increased in tg‐APPSwe mice relative to wild‐type littermates but, only in aged tg‐APPSwe mice did insulin decrease and normalize the current. Insulin effects on GABA signalling in hippoc al neurons are selective while multifaceted and context‐based. Not only is the response to insulin related to cell‐type, hippoc al axis‐location, age of animals and disease but also to the subtype of neuronal inhibition involved, synaptic or extrasynaptic GABA A receptors‐activated currents.
Publisher: Wiley
Date: 21-04-2006
DOI: 10.1111/J.1471-4159.2006.03811.X
Abstract: GABA is the main inhibitory neurotransmitter in the mammalian CNS. GABA in the brain is commonly associated with a fast, point-to-point form of signalling called synaptic transmission (phasic inhibition), but there is growing evidence that GABA participates in another, slower and more diffuse form of signalling often referred to as tonic inhibition. Unresolved questions regarding tonic neuronal inhibition concern activation and functional properties of extrasynaptic GABAA receptors (GABARex) present on neurones. Extrasynaptic receptors are exposed to submicromolar GABA concentrations and may modulate the overall excitability of neurones and neuronal networks. Here, we examined GABA-activated single-channel currents in dentate gyrus granule neurones in rat hippoc al slices. We activated three types (I, II, III) of GABARex channels by nanomolar GABA concentrations (EC50 I: 27 +/- 12 II: 4 +/- 3 III: 43 +/- 19 nm). The channels opened after a delay and the single-channel conductance was graded (gammamax I: 61 +/- 3 II: 85 +/- 8, III: 40 +/- 3 pS). The channels were differentially modulated by 1 microm diazepam, 200 nm zolpidem, 1 microm flumazenil and 50 nm THDOC (3alpha, 21-dihydroxy-5alpha-pregnan-20-one), consistent with the following minimal subunit composition of GABARex I alpha1betagamma2, GABARex II alpha4betagamma2 and GABARex III alphabetadelta channels.
Publisher: Cold Spring Harbor Laboratory
Date: 20-04-2023
DOI: 10.1101/2023.04.18.537327
Abstract: Metabolic programs of immune cells are closely linked to their effector functions 1 , where physiological molecules provide environmental cues and guidance 2–5 . Exactly how it happens is still being unraveled. Insulin maintains normal blood glucose levels 6 and glucose is the main source of energy and a precursor for many biomolecules in T cells 7, 8 , whereas γ-aminobutyric acid (GABA), best known as a neurotransmitter, is increasingly recognized as a regulatory molecule in the immune system 4, 9 . Here, we demonstrate that GABA-mediated reduction of metabolic activity and release of inflammatory molecules, including IFNγ and IL-10, was abolished in human CD4 + T cells, when the glucose concentration was elevated above normal levels. In a glucose concentration-dependent manner, insulin enhanced the GABA A receptors activated currents and GABA-dependent Ca 2+ influx. GABA decreased, whereas insulin maintained glycolysis but in a SGLT (Na + -glucose transporter)-dependent manner, revealing expression of SGLTs in activated CD4 + T cells. The SGLTs antagonist phlorizin, alone or together with GABA, restored the inhibition of IFNγ and IL-10 release in presence of high glucose. This study exposes concerted effects of GABA, glucose and insulin on CD4 + T cells metabolic activity and release of inflammatory molecules, and identifies a role for SGLTs in CD4 + T cells function.
Publisher: American Chemical Society (ACS)
Date: 12-01-2023
Publisher: Wildlife Disease Association
Date: 07-1986
DOI: 10.7589/0090-3558-22.3.389
Abstract: Serum electrolytes, urea nitrogen, creatinine, albumin and globulin were studied in fin whales (Balaenoptera physalus) caught by commercial whalers in the North Atlantic (Denmark Strait area). Blood s les were obtained by catchment or cardiac puncture within 5-15 min of death and analyzed using automated spectrophotometric methods and flame photometry. Osmolality was determined for two serum s les by a vapor pressure method. Linear regressions determined for each measured serum variable vs. chase time suggested that pursuit of the whales prior to capture had no substantive effect on measured serum chemistry. As in other cetaceans, serum sodium, chloride, urea nitrogen and osmolality were distinctly higher in the fin whale than in terrestrial mammals. The total concentration of serum proteins, however, was 1.4-1.8 g/dl lower, on average, than reported in small toothed whales, and was similar to that of domesticated animals. One animal in this population showed alterations in serum chemistry which were consistent with renal failure.
Publisher: Springer Science and Business Media LLC
Date: 26-11-2015
DOI: 10.1007/S00702-015-1446-9
Abstract: 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 Ca(2+) 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.
Publisher: Wiley
Date: 13-06-2020
DOI: 10.1002/HIPO.23245
Location: Australia
No related grants have been discovered for Bryndis Birnir.