Submicromolar copper (II) ions stimulate transretinal signaling in the isolated retina from wild type but not from Cav2.3-deficient mice

Abstract Background: So far, only indirect evidence exists for the pharmacoresistant R-type voltage-gated Ca2+ channel (VGCC) to be involved in transretinal signaling by triggering GABA-release onto ON-bipolar neurons. This release of inhibitory neurotransmitters was deduced from the sensitivity of the b-wave to stimulation by Ni2+, Zn2+ and Cu2+. To further confirm the interpretation of these findings, we compared the effects of Cu2+ application and chelation (using kainic acid, KA) on the neural retina from wildtype and Cav2.3-deficient mice. Furthermore, the immediately effect of KA on the ERG b-wave modulation was assessed.Methods: Transretinal signaling was recorded as an ERG from the superfused murine retina isolated from wildtype and Cav2.3-deficient mice.Results: In mice, the stimulating effect of 100 nM CuCl2 is absent in the retinae from Cav2.3-deficient mice, but prominent in Cav2.3-competent mice. Application of up to 3 mM tricine does not affect the murine b-wave in both genotypes, most likely because of chelating amino acids present in the murine nutrient solution. Application of 27 µM KA significantly increased the b-wave amplitude in wild type and Cav2.3 (-|-) mice. This effect can most likely be explained by the stimulation of endogenous KA-receptors described in horizontal, OFF-bipolar, amacrine or ganglion cells, which could not be fully blocked in the present study.Conclusion: Cu2+-dependent modulation of transretinal signaling only occurs in the murine retina from Cav2.3 competent mice, supporting the ideas derived from previous work in the bovine retina that R-type Ca2+ channels are involved in shaping transretinal responses during light perception.

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Submicromolar copper (II) ions stimulate transretinal signaling in the isolated retina from wild type but not from Cav2.3-deficient mice

10.21203/rs.2.16907/v2 ◽

2020 ◽

Author(s):

Toni Schneider ◽

Jan Niklas Lüke ◽

Felix Neumaier ◽

Serdar Alpdogan ◽

Jürgen Hescheler ◽

...

Keyword(s):

Ganglion Cells ◽

Indirect Evidence ◽

Gaba Release ◽

Light Perception ◽

Wild Type ◽

Inhibitory Neurotransmitters ◽

Bovine Retina ◽

Isolated Retina ◽

Deficient Mice ◽

Stimulation Of

Abstract Background : So far, only indirect evidence exists for the pharmacoresistant R-type voltage-gated Ca 2+ channel (VGCC) to be involved in transretinal signaling by triggering GABA-release onto ON-bipolar neurons. This release of inhibitory neurotransmitters was deduced from the sensitivity of the b-wave to stimulation by Ni 2+ , Zn 2+ and Cu 2+ . To further confirm the interpretation of these findings, we compared the effects of Cu 2+ application and chelation (using kainic acid, KA) on the neural retina from wild type and Ca v 2.3-deficient mice. Furthermore, the immediately effect of KA on the ERG b-wave modulation was assessed. Methods : Transretinal signaling was recorded as an ERG from the superfused murine retina isolated from wildtype and Ca v 2.3-deficient mice Results : In mice, the stimulating effect of 100 nM CuCl 2 is absent in the retinae from Ca v 2.3-deficient mice, but prominent in Ca v 2.3-competent mice. Application of up to 3 mM tricine does not affect the murine b-wave in both genotypes, most likely because of chelating amino acids present in the murine nutrient solution. Application of 27 µM KA significantly increased the b-wave amplitude in wild type and Ca v 2.3 (-|-) mice. This effect can most likely be explained by the stimulation of endogenous KA-receptors described in horizontal, OFF-bipolar, amacrine or ganglion cells, which could not be fully blocked in the present study. Conclusion: Cu 2+ dependent modulation of transretinal signaling only occurs in the murine retina from Ca v 2.3 competent mice, supporting the ideas derived from previous work in the bovine retina that R-type Ca 2+ channels are involved in shaping transretinal responses during light perception.

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Submicromolar copper (II) ions stimulate transretinal signaling in the isolated retina from wild type but not fromCav2.3-deficient mice

10.21203/rs.2.16907/v3 ◽

2020 ◽

Author(s):

Jan Niklas Lüke ◽

Felix Neumaier ◽

Serdar Alpdogan ◽

Jürgen Hescheler ◽

Toni Schneider ◽

...

Keyword(s):

Ganglion Cells ◽

Indirect Evidence ◽

Gaba Release ◽

Light Perception ◽

Wild Type ◽

Inhibitory Neurotransmitters ◽

Bovine Retina ◽

Isolated Retina ◽

Deficient Mice ◽

Stimulation Of

Abstract Background: So far, only indirect evidence exists for the pharmacoresistant R-type voltage-gated Ca2+ channel (VGCC) to be involved in transretinal signaling by triggering GABA-release onto ON-bipolar neurons. This release of inhibitory neurotransmitters was deduced from the sensitivity of the b-wave to stimulation by Ni2+, Zn2+ and Cu2+. To further confirm the interpretation of these findings, we compared the effects of Cu2+ application and chelation (using kainic acid, KA) on the neural retina from wild type and Cav2.3-deficient mice. Furthermore, the immediately effect of KA on the ERG b-wave modulation was assessed.Methods: Transretinal signaling was recorded as an ERG from the superfused murine retina isolated from wildtype and Cav2.3-deficient miceResults: In mice, the stimulating effect of 100 nM CuCl2 is absent in the retinae from Cav2.3-deficient mice, but prominent in Cav2.3-competent mice. Application of up to 3 mM tricine does not affect the murine b-wave in both genotypes, most likely because of chelating amino acids present in the murine nutrient solution. Application of 27 µM KA significantly increased the b-wave amplitude in wild type and Cav2.3 (-|-) mice. This effect can most likely be explained by the stimulation of endogenous KA-receptors described in horizontal, OFF-bipolar, amacrine or ganglion cells, which could not be fully blocked in the present study.Conclusion: Cu2+ dependent modulation of transretinal signaling only occurs in the murine retina from Cav2.3 competent mice, supporting the ideas derived from previous work in the bovine retina that R-type Ca2+ channels are involved in shaping transretinal responses during light perception.

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Submicromolar copper (II) ions stimulate transretinal signaling in the isolated retina from wild type but not from Cav2.3-deficient mice

10.21203/rs.2.16907/v1 ◽

2019 ◽

Author(s):

Toni Schneider ◽

Jan Niklas Lüke ◽

Felix Neumaier ◽

Serdar Alpdogan ◽

Jürgen Hescheler ◽

...

Keyword(s):

Ganglion Cells ◽

Indirect Evidence ◽

Gaba Release ◽

Wild Type ◽

Inhibitory Neurotransmitters ◽

Bovine Retina ◽

Isolated Retina ◽

Deficient Mice ◽

Ca2 Channels ◽

Stimulation Of

Abstract Background: So far, only indirect evidence exists for the pharmacoresistant R-type voltage-gated Ca2+ channel (VGCC) to be involved in transretinal signaling by triggering GABA-release onto ON-bipolar neurons. This release of inhibitory neurotransmitters was deduced from the sensitivity of the b-wave to stimulation by Ni2+ , Zn2+ and Cu2+ . To further confirm the interpretation of these findings, we compared the effects of Cu2+ application and chelation on the neural retina from wildtype and Cav2.3-deficient mice. Furthermore, the effect of kainic acid (KA) on the ERG b-wave modulation was assessed. Methods: Transretinal signaling was recorded as an ERG from the superfused murine retina isolated from wildtype and Cav2.3-deficient mice Results: In mice, the stimulating effect of 100 nM CuCl2 is absent in the retinae from Cav2.3-deficient mice, but prominent in Cav2.3-competent mice. Application of up to 3 mM tricine does not affect the murine b-wave in both genotypes, most likely because of chelating amino acids present in the murine nutrient solution. Application of 27 µM KA significantly increased the b-wave amplitude in wild type and Cav2.3 (-|-) mice. This effect can most likely be explained by the stimulation of endogenous KA-receptors described in horizontal, OFF-bipolar, amacrine or ganglion cells, which could not be fully blocked in the present study. Conclusion: Cu2+ dependent modulation of transretinal signaling only occurs in the murine retina from Cav2.3 competent mice, supporting the ideas derived from previous work in the bovine retina that R-type Ca2+ channels are involved in shaping transretinal responses during light perception.

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GABA Transporter-1 (GAT1)-Deficient Mice: Differential Tonic Activation of GABAA Versus GABAB Receptors in the Hippocampus

Journal of Neurophysiology ◽

10.1152/jn.00240.2003 ◽

2003 ◽

Vol 90 (4) ◽

pp. 2690-2701 ◽

Cited By ~ 149

Author(s):

Kimmo Jensen ◽

Chi-Sung Chiu ◽

Irina Sokolova ◽

Henry A. Lester ◽

Istvan Mody

Keyword(s):

Gaba Release ◽

Gabab Receptors ◽

Acid Decarboxylase ◽

Wild Type ◽

Gaba Transporter ◽

Inhibitory Neurotransmitter ◽

Gaba Transporters ◽

Gaba Transporter 1 ◽

Glutamic Acid Decarboxylase 65 ◽

Deficient Mice

After its release from interneurons in the CNS, the major inhibitory neurotransmitter GABA is taken up by GABA transporters (GATs). The predominant neuronal GABA transporter GAT1 is localized in GABAergic axons and nerve terminals, where it is thought to influence GABAergic synaptic transmission, but the details of this regulation are unclear. To address this issue, we have generated a strain of GAT1-deficient mice. We observed a large increase in a tonic postsynaptic hippocampal GABAA receptor-mediated conductance. There was little or no change in the waveform or amplitude of spontaneous inhibitory postsynaptic currents (IPSCs) or miniature IPSCs. In contrast, the frequency of quantal GABA release was one-third of wild type (WT), although the densities of GABAA receptors, GABAB receptors, glutamic acid decarboxylase 65 kDa, and vesicular GAT were unaltered. The GAT1-deficient mice lacked a presynaptic GABAB receptor tone, present in WT mice, which reduces the frequency of spontaneous IPSCs. We conclude that GAT1 deficiency leads to enhanced extracellular GABA levels resulting in an overactivation of GABAA receptors responsible for a postsynaptic tonic conductance. Chronically elevated GABA levels also downregulate phasic GABA release and reduce presynaptic signaling via GABAB receptors thus causing an enhanced tonic and a diminished phasic inhibition.

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Neutralization or Absence of the Interleukin-23 Pathway Does Not Compromise Immunity to Mycobacterial Infection

Infection and Immunity ◽

10.1128/iai.00621-06 ◽

2006 ◽

Vol 74 (11) ◽

pp. 6092-6099 ◽

Cited By ~ 54

Author(s):

Alissa A. Chackerian ◽

Shi-Juan Chen ◽

Scott J. Brodie ◽

Jeanine D. Mattson ◽

Terrill K. McClanahan ◽

...

Keyword(s):

Immune Response ◽

Secondary Infection ◽

Mycobacterial Infection ◽

Effective Control ◽

Bacterial Burden ◽

Wild Type ◽

Interleukin 23 ◽

Deficient Mice ◽

Stimulation Of

ABSTRACT Interleukin-23 (IL-23), a member of the IL-12 family, is a heterodimeric cytokine that is composed of the p40 subunit of IL-12 plus a unique p19 subunit. IL-23 is critical for autoimmune inflammation, in part due to its stimulation of the proinflammatory cytokine IL-17A. It is less clear, however, if IL-23 is required during the immune response to pathogens. We examined the role of IL-23 during Mycobacterium bovis BCG infection. We found that IL-23 reduces the bacterial burden and promotes granuloma formation when IL-12 is absent. However, IL-23 does not contribute substantially to host resistance when IL-12 is present, as the ability to control bacterial growth and form granulomata is not affected in IL-23p19-deficient mice and mice treated with a specific anti-IL-23p19 antibody. IL-23p19-deficient mice are also able to mount an effective memory response to secondary infection with BCG. While IL-23p19-deficient mice do not produce IL-17A, this cytokine is not necessary for effective control of infection, and antibody blocking of IL-17A in both wild-type and IL-12-deficient mice also has little effect on the bacterial burden. These data suggest that IL-23 by itself does not play an essential role in the protective immune response to BCG infection; however, the presence of IL-23 can partially compensate for the absence of IL-12. Furthermore, neutralization of IL-23 or IL-17A does not increase susceptibility to mycobacterial BCG infection.

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Norrin Protects Retinal Ganglion Cells from Excitotoxic Damage via the Induction of Leukemia Inhibitory Factor

Cells ◽

10.3390/cells9020277 ◽

2020 ◽

Vol 9 (2) ◽

pp. 277 ◽

Cited By ~ 3

Author(s):

Stefan Kassumeh ◽

Stephanie Leopold ◽

Rudolf Fuchshofer ◽

Carina N. Thomas ◽

Siegfried G. Priglinger ◽

...

Keyword(s):

Protective Factors ◽

Mrna Expression ◽

Retinal Ganglion Cells ◽

Leukemia Inhibitory Factor ◽

Ganglion Cells ◽

Inhibitory Factor ◽

Retinal Ganglion ◽

Wild Type ◽

Excitotoxic Damage ◽

Deficient Mice

Purpose: To investigate whether and how leukemia inhibitory factor (Lif) is involved in mediating the neuroprotective effects of Norrin on retinal ganglion cells (RGC) following excitotoxic damage. Norrin is a secreted protein that protects RGC from N-methyl-d-aspartate (NMDA)-mediated excitotoxic damage, which is accompanied by increased expression of protective factors such as Lif, Edn2 and Fgf2. Methods: Lif-deficient mice were injected with NMDA in one eye and NMDA plus Norrin into the other eye. RGC damage was investigated and quantified by TUNEL labeling 24 h after injection. Retinal mRNA expression was analyzed by quantitative real-time polymerase chain reaction following retinal treatment. Results: After intravitreal injection of NMDA and Norrin in wild-type mice approximately 50% less TUNEL positive cells were observed in the RGC layer when compared to NMDA-treated littermates, an effect which was lost in Lif-deficient mice. The mRNA expression for Gfap, a marker for Müller cell gliosis, as well as Edn2 and Fgf2 was induced in wild-type mice following NMDA/Norrin treatment but substantially blocked in Lif-deficient mice. Conclusions: Norrin mediates its protective properties on RGC via Lif, which is required to enhance Müller cell gliosis and to induce protective factors such as Edn2 or Fgf2.

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Neuronal GABA release and GABA inhibition of ACh release in guinea pig urinary bladder

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1984.246.4.r502 ◽

1984 ◽

Vol 246 (4) ◽

pp. R502-R509 ◽

Cited By ~ 1

Author(s):

M. Kusunoki ◽

K. Taniyama ◽

C. Tanaka

Keyword(s):

Electrical Stimulation ◽

Urinary Bladder ◽

Gaba Receptors ◽

Ganglion Cells ◽

Regional Distribution ◽

Cholinergic Neurons ◽

Gaba Release ◽

Gamma Aminobutyric Acid ◽

Ach Release ◽

Stimulation Of

gamma-Aminobutyric acid (GABA) and glutamate decarboxylase (GAD) are present in the urinary bladder of guinea pigs, and the possible correlation in regional distribution between GABA, GAD, and the number of vesical ganglion cells was studied. Electrical stimulation of the bladder strips produced an increase in the calcium-dependent and tetrodotoxin-sensitive [3H]GABA release and contractions in the strips preloaded with [3H]GABA. Nicotine, acetylcholine chloride (ACh), and hexamethonium did not significantly alter the release of [3H]GABA. Bicuculline significantly enhanced [3H]ACh release and cholinergic components of contractions evoked by electrical stimulation of the bladder strips preloaded with [3H]choline, thereby suggesting that this compound antagonizes the effect of endogenous GABA released during stimulation. GABA and muscimol but not baclofen reduced both the [3H]ACh release and contractions evoked by nicotine. These effects of GABA were antagonized by bicuculline and furosemide but not by alpha- and beta-adrenergic blockers. These findings suggest that GABA may be a noncholinergic nonadrenergic inhibitory neurotransmitter in the urinary bladder. The motility of the urinary bladder is thus inhibited by reducing the release of ACh from the postganglionic cholinergic neurons through bicuculline-sensitive GABA receptors probably associated with the chloride ion channel.

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Defective coupling of apical PTH receptors to phospholipase C prevents internalization of the Na+-phosphate cotransporter NaPi-IIa in Nherf1-deficient mice

AJP Cell Physiology ◽

10.1152/ajpcell.00126.2006 ◽

2007 ◽

Vol 292 (2) ◽

pp. C927-C934 ◽

Cited By ~ 67

Author(s):

Paola Capuano ◽

Desa Bacic ◽

Marcel Roos ◽

Serge M. Gisler ◽

Gerti Stange ◽

...

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Proximal Tubule ◽

Phospholipase C ◽

Wild Type ◽

Phosphate Reabsorption ◽

Kinase C ◽

Deficient Mice ◽

Stimulation Of

Phosphate reabsorption in the renal proximal tubule occurs mostly via the type IIa Na+-phosphate cotransporter (NaPi-IIa) in the brush border membrane (BBM). The activity and localization of NaPi-IIa are regulated, among other factors, by parathyroid hormone (PTH). NaPi-IIa interacts in vitro via its last three COOH-terminal amino acids with the PDZ protein Na+/H+-exchanger isoform 3 regulatory factor (NHERF)-1 (NHERF1). Renal phosphate reabsorption in Nherf1-deficient mice is altered, and NaPi-IIa expression in the BBM is reduced. In addition, it has been proposed that NHERF1 and NHERF2 are important for the coupling of PTH receptors (PTHRs) to phospholipase C (PLC) and the activation of the protein kinase C pathway. We tested the role of NHERF1 in the regulation of NaPi-IIa by PTH in Nherf1-deficient mice. Immunohistochemistry and Western blotting demonstrated that stimulation of apical and basolateral receptors with PTH-(1–34) led to internalization of NaPi-IIa in wild-type and Nherf1-deficient mice. Stimulation of only apical receptors with PTH-(3–34) failed to induce internalization in Nherf1-deficient mice. Expression and localization of apical PTHRs were similar in wild-type and Nherf1-deficient mice. Activation of the protein kinase C- and A-dependent pathways with 1,2-dioctanoyl- sn-glycerol or 8-bromo-cAMP induced normal internalization of NaPi-IIa in wild-type, as well as Nherf1-deficient, mice. Stimulation of PLC activity due to apical PTHRs was impaired in Nherf1-deficient mice. These data suggest that NHERF1 in the proximal tubule is important for PTH-induced internalization of NaPi-IIa and, specifically, couples the apical PTHR to PLC.

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