Immunosuppression by N-Methyl-<scp>d</scp>-Aspartate Receptor Antagonists Is Mediated through Inhibition of Kv1.3 and KCa3.1 Channels in T Cells

Kahlfuß, Sascha; Simma, Narasimhulu; Mankiewicz, Judith; Bose, Tanima; Lowinus, Theresa; Klein-Heßling, Stefan; Sprengel, Rolf; Schraven, Burkhart; Heisenberg, Martin; Bommhardt, Ursula

doi:10.1128/mcb.01273-13

Cited by 48 publications

(51 citation statements)

References 59 publications

(75 reference statements)

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“…Intriguingly, we identified a unique aberrant spiking event associated with individual Dilt pretreatment. We also found non-specific effects of Mem and Dilt on K 2P , Na + , voltage-gated K + and Ca 2+ -activated K + channels, as reported by previous studies (Bukanova & Solntseva, 1997; He & Bausch, 2014; Ito et al, 2010; Kahlfuss et al, 2014; Kimura et al, 1983; Takahira et al, 2005). Further investigations are needed to determine if such non-Ca 2+ channel effects of the two blockers also actually contribute to the aberrant firing events.…”

Section: Discussionsupporting

confidence: 90%

“…Interestingly, combined Dilt/Mem pretreatment also induced an increase in the 1/2 amplitude duration of evoked action potentials in neurons from both non-Tg and HIV-1 Tg rats as compared to those from SAL-pretreated non-Tg and HIV-1 Tg rats. This increase in the 1/2 amplitude duration might result from non-specific inhibitory effects of Dilt and/or Mem on voltage-gated K + channels and Ca 2+ -activated K + channels, respectively (Bukanova & Solntseva, 1997; Ito et al, 2010; Kahlfuss et al, 2014). Combined chronic Dilt/Mem pretreatment did not significantly affect the RMP, threshold, and AHP ( Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

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Combined chronic blockade of hyper-active L-type calcium channels and NMDA receptors ameliorates HIV-1 associated hyper-excitability of mPFC pyramidal neurons

Khodr

Chen

Davé

et al. 2016

Neurobiology of Disease

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Human Immunodeficiency Virus type 1 (HIV-1) infection induces neurological and neuropsychological deficits, which are associated with dysregulation of the medial prefrontal cortex (mPFC) and other vulnerable brain regions. We evaluated the impact of HIV infection in the mPFC and the therapeutic potential of targeting over-active voltage-gated L-type Ca2+ channels (L-channel) and NMDA receptors (NMDAR), as modeled in HIV-1 transgenic (Tg) rats. Whole-cell patch-clamp recording was used to assess the membrane properties and voltage-sensitive Ca2+ potentials (Ca2+ influx) in mPFC pyramidal neurons. Neurons from HIV-1 Tg rats displayed reduced rheobase, spike amplitude and inwardly-rectifying K+ influx, increased numbers of action potentials, and a trend of aberrant firing compared to those from non-Tg control rats. Neuronal hyper-excitation was associated with abnormally-enhanced Ca2+ influx (independent of NMDAR), which was eliminated by acute L-channel blockade. Combined chronic blockade of over-active L-channels and NMDARs with open-channel blockers abolished HIV effects on spiking, aberrant firing and Ca2+ potential half-amplitude duration, though not the reduced inward rectification. In contrast, individual chronic blockade of over-active L-channels or NMDARs did not alleviate HIV-induced mPFC hyper-excitability. These studies demonstrate that HIV alters mPFC neuronal activity by dysregulating membrane excitability and Ca2+ influx through the L-channels. This renders these neurons more susceptible and vulnerable to excitatory stimuli, and could contribute to HIV-associated neuropathogenesis. Combined targeting of over-active L-channels/NMDARs alleviates HIV-induced dysfunction of mPFC pyramidal neurons, emphasizing a potential novel therapeutic strategy that may effectively decrease HIV-induced Ca2+ dysregulation in the mPFC.

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Section: Discussionsupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Combined chronic blockade of hyper-active L-type calcium channels and NMDA receptors ameliorates HIV-1 associated hyper-excitability of mPFC pyramidal neurons

Khodr

Chen

Davé

et al. 2016

Neurobiology of Disease

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“…Glutamate was originally found as a major excitatory neurotransmitter in the CNS and can also act as a signaling molecule in other tissues (40). Recent studies have shown that glutamate could regulate the activation and proliferation of T cells through the glutamate receptor NMDAR (41). Therefore, we examined the effect of the NMDAR inhibitor MK-801 on IMC activation.…”

Section: Glutamate Can Promote Late-stage Imc Activation Through Nmdarmentioning

confidence: 99%

Immunosuppressive Immature Myeloid Cell Generation Is Controlled by Glutamine Metabolism in Human Cancer

Sun

Chen

et al. 2019

Cancer Immunology Research

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Tumor-associated myeloid cells are one of the prominent components of solid tumors, serving as major immune regulators for the tumor microenvironment (TME) and an obstacle for immune-checkpoint blocking (ICB) therapy. However, it remains unclear how metabolic processes regulate the generation of suppressive myeloid cells in the TME. Here, we found that hematopoietic precursor cells are enriched in the tissues of several types of human cancer and can differentiate into immature myeloid cells (IMC). Tumor-infiltrating IMCs are highly immunosuppressive, glycolytic, and proliferative, as indicated by high levels of M-CSFR, Glut1, and Ki67. To elucidate the role of metabolism in regulating the generation of IMCs, we induced suppressive IMCs from hematopoietic precursor cells with GM-CSF and G-CSF in vitro. We found that the generation of suppressive IMCs was accompanied by increased glycolysis, but not affected by glucose deprivation due to alternative catabolism. Generation of IMCs relied on glutaminolysis, regardless of glucose availability. Glutamine metabolism not only supported the expansion of IMCs with glutamine-derived a-ketoglutarate but also regulated the suppressive capacity through the glutamate-NMDA receptor axis. Moreover, inhibition of glutaminase GLS1 enhanced the therapeutic efficacy of anti-PD-L1 treatment, with reduced arginase 1 þ myeloid cells, increased CD8 þ , IFNg þ and granzyme B þ T cells, and delayed tumor growth in an ICB-resistant mouse model. Our work identified a novel regulatory mechanism of glutamine metabolism in controlling the generation of suppressive IMCs in the TME.

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“…In vitro studies showed that Memantine, exhibited antiplatelet activity. Kahlfuß et al, [29] reported that NMDAR antagonists have profound effects on T-cell function.…”

Section: Discussionmentioning

confidence: 99%

Adverse Effects of Memantine

Shams

Khairy

Saleh

et al. 2017

Zagazig Veterinary Journal

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The current study covers key issues related to memantine's toxicity (0.36 mg/kg, P.O. once daily) and its effect on liver, Kidney, blood and antioxidant enzymes for three weeks. Then tissue and blood samples were collected at the 1st, 2nd and 3rd weeks post-treatment. Our results indicated that Memantine has hepato-nephrotoxicity and elevation of liver enzymes (ALT, AST and ALP), creatinine, urea and uric acid. Obvious decline in all blood parameters with respectable decline in antioxidant enzyme like CAT, SOD, GPX and a significant increase in MDA. Histopathology revealed hepatic steatosis and increase the apoptotic and necrotic cells mostly within the centrolobular, as. Also, tubular basophilia and interstitial nephritis were observed. Therefore, Memantine should be used with caution with hepatic or people with kidney problems.

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Immunosuppression by N-Methyl-d-Aspartate Receptor Antagonists Is Mediated through Inhibition of K_v1.3 and K_Ca3.1 Channels in T Cells

Cited by 48 publications

References 59 publications

Combined chronic blockade of hyper-active L-type calcium channels and NMDA receptors ameliorates HIV-1 associated hyper-excitability of mPFC pyramidal neurons

Combined chronic blockade of hyper-active L-type calcium channels and NMDA receptors ameliorates HIV-1 associated hyper-excitability of mPFC pyramidal neurons

Immunosuppressive Immature Myeloid Cell Generation Is Controlled by Glutamine Metabolism in Human Cancer

Adverse Effects of Memantine

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Immunosuppression by N-Methyl-d-Aspartate Receptor Antagonists Is Mediated through Inhibition of Kv1.3 and KCa3.1 Channels in T Cells

Cited by 48 publications

References 59 publications

Combined chronic blockade of hyper-active L-type calcium channels and NMDA receptors ameliorates HIV-1 associated hyper-excitability of mPFC pyramidal neurons

Combined chronic blockade of hyper-active L-type calcium channels and NMDA receptors ameliorates HIV-1 associated hyper-excitability of mPFC pyramidal neurons

Immunosuppressive Immature Myeloid Cell Generation Is Controlled by Glutamine Metabolism in Human Cancer

Adverse Effects of Memantine

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Product

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Immunosuppression by N-Methyl-d-Aspartate Receptor Antagonists Is Mediated through Inhibition of K_v1.3 and K_Ca3.1 Channels in T Cells