scholarly journals Calbindin regulates Kv4.1 trafficking and excitability of dentate granule cells via CaMKII-dependent phosphorylation

2021 ◽  
Author(s):  
Kyung-Ran Kim ◽  
Hyeon-Ju Jeong ◽  
Yoonsub Kim ◽  
Seung Yeon Lee ◽  
Yujin Kim ◽  
...  
Keyword(s):  
Neuronal Excitability ◽  
Granule Cells ◽  
Critical Role ◽  
Surface Expression ◽  
Knock Out ◽  
Dentate Granule Cells ◽  
Surface Localization ◽  
K Current ◽  
Knock Out Mice ◽  
Neuronal Functions

Calbindin, a major Ca2+ buffer in dentate granule cells (GCs), plays a critical role in shaping Ca2+ signals, yet how it regulates neuronal functions remains largely unknown. Here, we found that calbindin knock-out mice (CBKO) exhibited hyperexcitability in dentate GCs and impaired pattern separation, which was concurrent with reduced K+ current due to downregulated surface expression of Kv4.1. Consistently, manipulation of the calbindin expression in HT22 led to changes in CaMKII activation and the level of surface localization of Kv4.1 through phosphorylation at serine 555, confirming the mechanism underlying neuronal hyperexcitability in CBKO. We also discovered that Ca2+ buffering capacity was significantly reduced in the GCs of Tg2576 to the level of CBKO GCs, and this reduction was restored to normal levels by antioxidants, suggesting that calbindin is a target of oxidative stress. Our data suggest that regulation of CaMKII signaling by Ca2+ buffer is crucial for neuronal excitability regulation.

scholarly journals Calbindin regulates Kv4.1 trafficking and excitability in dentate granule cells via CaMKII-dependent phosphorylation

2021 ◽  
Author(s):  
Kyung-Ran Kim ◽  
Hyeon-Ju Jeong ◽  
Yoonsub Kim ◽  
Seung Yeon Lee ◽  
Yujin Kim ◽  
...  
Keyword(s):  
Neuronal Excitability ◽  
Granule Cells ◽  
Critical Role ◽  
Surface Expression ◽  
Neuronal Function ◽  
Ht22 Cells ◽  
Dentate Granule Cells ◽  
Surface Localization ◽  
Camkii Activation ◽  
Tg2576 Mice

AbstractCalbindin, a major Ca2+ buffer in dentate granule cells (GCs), plays a critical role in shaping Ca2+ signals, yet how it regulates neuronal function remains largely unknown. Here, we found that calbindin knockout (CBKO) mice exhibited dentate GC hyperexcitability and impaired pattern separation, which co-occurred with reduced K+ current due to downregulated surface expression of Kv4.1. Relatedly, manipulation of calbindin expression in HT22 cells led to changes in CaMKII activation and the level of surface localization of Kv4.1 through phosphorylation at serine 555, confirming the mechanism underlying neuronal hyperexcitability in CBKO mice. We also discovered that Ca2+ buffering capacity was significantly reduced in the GCs of Tg2576 mice to the level of CBKO GCs, and this reduction was restored to normal levels by antioxidants, suggesting that calbindin is a target of oxidative stress. Our data suggest that the regulation of CaMKII signaling by Ca2+ buffering is crucial for neuronal excitability regulation.

scholarly journals PKA-RIIβ autophosphorylation modulates PKA activity and seizure phenotypes in mice

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Jingliang Zhang ◽  
Chenyu Zhang ◽  
Xiaoling Chen ◽  
Bingwei Wang ◽  
Weining Ma ◽  
...  
Keyword(s):  
Therapeutic Target ◽  
Neurological Disorders ◽  
Neuronal Excitability ◽  
Granule Cells ◽  
Critical Role ◽  
Intrinsic Excitability ◽  
Seizure Susceptibility ◽  
Seizure Onset ◽  
Potential Therapeutic Target ◽  
Seizure Model

AbstractTemporal lobe epilepsy (TLE) is one of the most common and intractable neurological disorders in adults. Dysfunctional PKA signaling is causally linked to the TLE. However, the mechanism underlying PKA involves in epileptogenesis is still poorly understood. In the present study, we found the autophosphorylation level at serine 114 site (serine 112 site in mice) of PKA-RIIβ subunit was robustly decreased in the epileptic foci obtained from both surgical specimens of TLE patients and seizure model mice. The p-RIIβ level was negatively correlated with the activities of PKA. Notably, by using a P-site mutant that cannot be autophosphorylated and thus results in the released catalytic subunit to exert persistent phosphorylation, an increase in PKA activities through transduction with AAV-RIIβ-S112A in hippocampal DG granule cells decreased mIPSC frequency but not mEPSC, enhanced neuronal intrinsic excitability and seizure susceptibility. In contrast, a reduction of PKA activities by RIIβ knockout led to an increased mIPSC frequency, a reduction in neuronal excitability, and mice less prone to experimental seizure onset. Collectively, our data demonstrated that the autophosphorylation of RIIβ subunit plays a critical role in controlling neuronal and network excitabilities by regulating the activities of PKA, providing a potential therapeutic target for TLE.

scholarly journals Methylation determines the extracellular calcium sensitivity of the leak channel NALCN in hippocampal dentate granule cells

2019 ◽  
Vol 51 (10) ◽  
pp. 1-14 ◽  
Author(s):  
Seul-Yi Lee ◽  
Tuan Anh Vuong ◽  
Xianlan Wen ◽  
Hyeon-Ju Jeong ◽  
Hyun-Kyung So ◽  
...  
Keyword(s):  
Neuronal Excitability ◽  
Granule Cells ◽  
Phosphorylation Site ◽  
Calcium Sensitivity ◽  
Arginine Methylation ◽  
Resting Membrane Potential ◽  
Leak Channel ◽  
Dentate Granule Cells ◽  
Severe Intellectual Disability

Abstract The sodium leak channel NALCN is a key player in establishing the resting membrane potential (RMP) in neurons and transduces changes in extracellular Ca2+ concentration ([Ca2+]e) into increased neuronal excitability as the downstream effector of calcium-sensing receptor (CaSR). Gain-of-function mutations in the human NALCN gene cause encephalopathy and severe intellectual disability. Thus, understanding the regulatory mechanisms of NALCN is important for both basic and translational research. This study reveals a novel mechanism for NALCN regulation by arginine methylation. Hippocampal dentate granule cells in protein arginine methyltransferase 7 (PRMT7)-deficient mice display a depolarization of the RMP, decreased threshold currents, and increased excitability compared to wild-type neurons. Electrophysiological studies combined with molecular analysis indicate that enhanced NALCN activities contribute to hyperexcitability in PRMT7−/− neurons. PRMT7 depletion in HEK293T cells increases NALCN activity by shifting the dose-response curve of NALCN inhibition by [Ca2+]e without affecting NALCN protein levels. In vitro methylation studies show that PRMT7 methylates a highly conserved Arg1653 of the NALCN gene located in the carboxy-terminal region that is implicated in CaSR-mediated regulation. A kinase-specific phosphorylation site prediction program shows that the adjacent Ser1652 is a potential phosphorylation site. Consistently, our data from site-specific mutants and PKC inhibitors suggest that Arg1653 methylation might modulate Ser1652 phosphorylation mediated by CaSR/PKC-delta, leading to [Ca2+]e-mediated NALCN suppression. Collectively, these data suggest that PRMT7 deficiency decreases NALCN methylation at Arg1653, which, in turn, decreases CaSR/PKC-mediated Ser1652 phosphorylation, lifting NALCN inhibition, thereby enhancing neuronal excitability. Thus, PRMT7-mediated NALCN inhibition provides a potential target for the development of therapeutic tools for neurological diseases.

scholarly journals Behavioral role of PACAP signaling reflects its selective distribution in glutamatergic and GABAergic neuronal subpopulations

2020 ◽  
Author(s):  
Limei Zhang ◽  
Vito S. Hernández ◽  
Charles R. Gerfen ◽  
Sunny Z. Jiang ◽  
Lilian Zavala ◽  
...  
Keyword(s):  
Nervous System ◽  
Neuronal Excitability ◽  
Knock Out ◽  
Neuronal Markers ◽  
Glutamatergic Neurons ◽  
Sensory Modalities ◽  
New Perspective ◽  
Knock Out Mice ◽  
Transporter Expression

AbstractThe neuropeptide PACAP, acting as a co-transmitter, increases neuronal excitability, which may enhance anxiety and arousal associated with threat conveyed by multiple sensory modalities. The distribution of neurons expressing PACAP and its receptor, PAC1, throughout the mouse nervous system was determined, in register with expression of glutamatergic and GABAergic neuronal markers, to develop a coherent chemoanatomical picture of PACAP’s role in brain motor responses to sensory input. A circuit role for PACAP was tested by observing fos activation of brain neurons after olfactory threat cue in wild type and PACAP knockout mice. Neuronal activation, and behavioral response, were blunted in PACAP knock-out mice, accompanied by sharply down-regulated vesicular transporter expression in both GABAergic and glutamatergic neurons expressing PACAP and its receptor. This report signals a new perspective on the role of neuropeptide signaling in supporting excitatory and inhibitory neurotransmission in the nervous system within functionally coherent polysynaptic circuits.

scholarly journals Complement Factor C7 Contributes to Lung Immunopathology Caused byMycobacterium tuberculosis

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Kerry J. Welsh ◽  
Cole T. Lewis ◽  
Sydney Boyd ◽  
Michael C. Braun ◽  
Jeffrey K. Actor
Keyword(s):  
Post Infection ◽  
Critical Role ◽  
Complement Factor ◽  
Wild Type ◽  
Knock Out ◽  
Host Protection ◽  
Colony Forming Units ◽  
Knock Out Mice ◽  
The Complement System

Mycobacterium tuberculosis(MTB) remains a significant global health burden despite the availability of antimicrobial chemotherapy. Increasing evidence indicates a critical role of the complement system in the development of host protection against the bacillus, but few studies have specifically explored the function of the terminal complement factors. Mice deficient in complement C7 and wild-type C57BL/6 mice were aerosol challenged with MTB Erdman and assessed for bacterial burden, histopathology, and lung cytokine responses at days 30 and 60 post-infection. Macrophages isolated from C7 −/− and wild-type mice were evaluated for MTB proliferation and cytokine production. C7 −/− mice had significantly less liver colony forming units (CFUs) at day 30; no differences were noted in lung CFUs. The C7 deficient mice had markedly reduced lung occlusion with significantly increased total lymphocytes, decreased macrophages, and increased numbers of CD4+ cells 60 days post-infection. Expression of lung IFN-γand TNF-αwas increased at day 60 compared to wild-type mice. There were no differences in MTB-proliferation in macrophages isolated from wild-type and knock-out mice. These results indicate a role for complement C7 in the development of MTB induced immunopathology which warrants further investigation.

scholarly journals Calpain-1 and Calpain-2 in the Brain: New Evidence for a Critical Role of Calpain-2 in Neuronal Death

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2698
Author(s):  
Yubin Wang ◽  
Yan Liu ◽  
Xiaoning Bi ◽  
Michel Baudry
Keyword(s):  
Synaptic Plasticity ◽  
Critical Role ◽  
Protein Targets ◽  
Knock Out ◽  
Regulatory Pathways ◽  
Calcium Dependent ◽  
Binding Domains ◽  
Calpain 2 ◽  
Knock Out Mice ◽  
The Brain

Calpains are a family of soluble calcium-dependent proteases that are involved in multiple regulatory pathways. Our laboratory has focused on the understanding of the functions of two ubiquitous calpain isoforms, calpain-1 and calpain-2, in the brain. Results obtained over the last 30 years led to the remarkable conclusion that these two calpain isoforms exhibit opposite functions in the brain. Calpain-1 activation is required for certain forms of synaptic plasticity and corresponding types of learning and memory, while calpain-2 activation limits the extent of plasticity and learning. Calpain-1 is neuroprotective both during postnatal development and in adulthood, while calpain-2 is neurodegenerative. Several key protein targets participating in these opposite functions have been identified and linked to known pathways involved in synaptic plasticity and neuroprotection/neurodegeneration. We have proposed the hypothesis that the existence of different PDZ (PSD-95, DLG and ZO-1) binding domains in the C-terminal of calpain-1 and calpain-2 is responsible for their association with different signaling pathways and thereby their different functions. Results with calpain-2 knock-out mice or with mice treated with a selective calpain-2 inhibitor indicate that calpain-2 is a potential therapeutic target in various forms of neurodegeneration, including traumatic brain injury and repeated concussions.

Transient Neurophysiological Changes in CA3 Neurons and Dentate Granule Cells After Severe Forebrain Ischemia In Vivo

1998 ◽  
Vol 80 (6) ◽  
pp. 2860-2869 ◽  
Author(s):  
T. M. Gao ◽  
E. M. Howard ◽  
Z. C. Xu
Keyword(s):  
Synaptic Transmission ◽  
Neuronal Excitability ◽  
Granule Cells ◽  
Input Resistance ◽  
Cell Types ◽  
Forebrain Ischemia ◽  
Postsynaptic Potentials ◽  
Dentate Granule Cells ◽  
Ca3 Neurons

Gao, T. M., E. M. Howard, and Z. C. Xu. Transient neurophysiological changes in CA3 neurons and dentate granule cells after severe forebrain ischemia in vivo. J. Neurophysiol. 80: 2860–2869, 1998. The spontaneous activities, evoked synaptic responses, and membrane properties of CA3 pyramidal neurons and dentate granule cells in rat hippocampus were compared before ischemia and ≤7 days after reperfusion with intracellular recording and staining techniques in vivo. A four-vessel occlusion method was used to induce ∼14 min of ischemic depolarization. No significant change in spontaneous firing rate was observed in both cell types after reperfusion. The amplitude and slope of excitatory postsynaptic potentials (EPSPs) in CA3 neurons decreased to 50% of control values during the first 12 h reperfusion and returned to preischemic levels 24 h after reperfusion. The amplitude and slope of EPSPs in granule cells slightly decreased 24–36 h after reperfusion. The amplitude of inhibitory postsynaptic potentials in CA3 neurons transiently increased 24 h after reperfusion, whereas that in granule cells showed a transient decrease 24–36 h after reperfusion. The duration of spike width of CA3 and granule cells became longer than that of control values during the first 12 h reperfusion. The spike threshold of both cell types significantly increased 24–36 h after reperfusion, whereas the frequency of repetitive firing evoked by depolarizing current pulse was decreased during this period. No significant change in rheobase and input resistance was observed in CA3 neurons. A transient increase in rheobase and a transient decrease in input resistance were detected in granule cells 24–36 h after reperfusion. The amplitude of fast afterhyperpolarization in both cell types increased for 2 days after ischemia and returned to normal values 7 days after reperfusion. The results from this study indicate that the neuronal excitability and synaptic transmission in CA3 and granule cells are transiently suppressed after severe forebrain ischemia. The depression of synaptic transmission and neuronal excitability may provide protection for neurons after ischemic insult.

Liver Inflammatory Injury Initiated by DAMPs-TLR4-MyD88/TRIF-NFκB Signaling Pathway Is Involved in Monocrotaline-Induced HSOS

2019 ◽  
Vol 172 (2) ◽  
pp. 385-397 ◽  
Author(s):  
Zhenlin Huang ◽  
Minwei Chen ◽  
Mengjuan Wei ◽  
Bin Lu ◽  
Xiaojun Wu ◽  
...  
Keyword(s):  
Critical Role ◽  
Nuclear Accumulation ◽  
Histological Evaluation ◽  
Sinusoidal Obstruction Syndrome ◽  
Related Factor ◽  
Myeloperoxidase Activity ◽  
Nuclear Factor ◽  
Inflammatory Injury ◽  
Knock Out ◽  
Knock Out Mice

Abstract Hepatic sinusoidal obstruction syndrome (HSOS) causes considerable morbidity and mortality in clinic. Up to now, the molecular mechanisms involved in the development of HSOS still remain unclear. Here, we report that hepatic inflammation initiated by damage-associated molecular patterns (DAMPs) plays a critical role in the development of HSOS. Monocrotaline (MCT) belongs to pyrrolizidine alkaloids. Monocrotaline-induced HSOS in mice and rats was evidenced by the increased serum alanine/aspartate aminotransferase (ALT/AST) activities, the elevated hepatic metalloproteinase 9 (MMP9) expression, and results from liver histological evaluation and scanning electron microscope observation. However, MCT-induced HSOS was markedly attenuated in myeloid differentiation primary response gene 88 (MyD88), TIR-domain-containing adapter-inducing interferon-β (TRIF) and toll like receptor 4 (TLR4) knock-out mice. Monocrotaline increased liver myeloperoxidase activity, serum contents of proinflammatory cytokines, hepatic aggregation of immune cells, and nuclear accumulation of nuclear factor κB (NFκB). However, these inflammatory responses induced by MCT were all diminished in MyD88, TRIF, and TLR4 knock-out mice. Monocrotaline elevated serum contents of DAMPs including high mobility group box 1 (HMGB1) and heat shock protein 60 (HSP60) both in mice and in rats. HSOS was markedly exacerbated and serum contents of HMGB1 and HSP60 were elevated in nuclear factor erythroid 2-related factor 2 (Nrf2) knock-out mice treated with MCT. Our findings indicate that hepatic inflammatory injury mediated by DAMPs-initiated TLR4-MyD88/TRIF-NFκB inflammatory signal pathway plays an important role in HSOS development.

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