scholarly journals SUMO modification of cell surface Kv2.1 potassium channels regulates the activity of rat hippocampal neurons

2011 ◽  
Vol 137 (5) ◽  
pp. 441-454 ◽  
Author(s):  
Leigh D. Plant ◽  
Evan J. Dowdell ◽  
Irina S. Dementieva ◽  
Jeremy D. Marks ◽  
Steve A.N. Goldstein
Keyword(s):  
Potassium Channels ◽  
Cell Surface ◽  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Voltage Gated ◽  
Sumo Modification ◽  
Maximal Activation ◽  
Sumo Pathway ◽  
Activity Dependent ◽  
The Brain

Voltage-gated Kv2.1 potassium channels are important in the brain for determining activity-dependent excitability. Small ubiquitin-like modifier proteins (SUMOs) regulate function through reversible, enzyme-mediated conjugation to target lysine(s). Here, sumoylation of Kv2.1 in hippocampal neurons is shown to regulate firing by shifting the half-maximal activation voltage (V1/2) of channels up to 35 mV. Native SUMO and Kv2.1 are shown to interact within and outside channel clusters at the neuronal surface. Studies of single, heterologously expressed Kv2.1 channels show that only K470 is sumoylated. The channels have four subunits, but no more than two non-adjacent subunits carry SUMO concurrently. SUMO on one site shifts V1/2 by 15 mV, whereas sumoylation of two sites produces a full response. Thus, the SUMO pathway regulates neuronal excitability via Kv2.1 in a direct and graded manner.

scholarly journals Potassium channels contribute to activity-dependent scaling of dendritic inhibition

2017 ◽  
Author(s):  
Jeremy T. Chang ◽  
Michael J. Higley
Keyword(s):  
Potassium Channels ◽  
Neuronal Activity ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Critical Role ◽  
Pyramidal Cells ◽  
Gabaergic Inhibition ◽  
Voltage Gated ◽  
The Impact ◽  
Activity Dependent

AbstractGABAergic inhibition plays a critical role in the regulation of neuronal activity. In the neocortex, inhibitory interneurons that target the dendrites of pyramidal cells influence both electrical and biochemical postsynaptic signaling. Voltage-gated ion channels strongly shape dendritic excitability and the integration of excitatory inputs, but their contribution to GABAergic signaling is less well understood. By combining 2-photon calcium imaging and focal GABA uncaging, we show that voltage-gated potassium channels normally suppress the GABAergic inhibition of calcium signals evoked by back-propagating action potentials in dendritic spines and shafts of cortical pyramidal neurons. Moreover, the voltage-dependent inactivation of these channels leads to enhancement of dendritic calcium inhibition following somatic spiking. Computational modeling reveals that the enhancement of calcium inhibition involves an increase in action potential depolarization coupled with the nonlinear relationship between membrane voltage and calcium channel activation. Overall, our findings highlight the interaction between intrinsic and synaptic properties and reveal a novel mechanism for the activity-dependent scaling of GABAergic inhibition.Significance StatementGABAergic inhibition potently regulates neuronal activity in the neocortex. How such inhibition interacts with the intrinsic electrophysiological properties of single neurons is not well-understood. Here we investigate the ability of voltage-gated potassium channels to regulate the impact of GABAergic inhibition in the dendrites of neocortical pyramidal neurons. Our results show that potassium channels normally reduce inhibition directed towards pyramidal neuron dendrites. However, these channels are inactivated by strong neuronal activity, leading to an enhancement of GABAergic potency and limiting the corresponding influx of dendritic calcium. Our findings illustrate a previously unappreciated relationship between neuronal excitability and GABAergic inhibition.

scholarly journals The Palmitoyl Acyltransferase ZDHHC14 Controls Kv1-Family Potassium Channel Clustering at the Axon Initial Segment

2020 ◽  
Author(s):  
Shaun S. Sanders ◽  
Luiselys M. Hernandez ◽  
Heun Soh ◽  
Santi Karnam ◽  
Randall S. Walikonis ◽  
...  
Keyword(s):  
Potassium Channels ◽  
Hippocampal Neurons ◽  
Initial Segment ◽  
Neuronal Excitability ◽  
Pdz Domain ◽  
Axon Initial Segment ◽  
Type I ◽  
Action Potential Firing ◽  
Potential Firing ◽  
Palmitoyl Acyltransferase

AbstractThe palmitoyl acyltransferase (PAT) ZDHHC14 is highly expressed in the hippocampus and is the only PAT predicted to bind Type I PDZ domain-containing proteins. However, ZDHHC14’s neuronal roles are unknown. Here, we identify the PDZ domain-containing Membrane-associated Guanylate Kinase (MaGUK) PSD93 as a direct ZDHHC14 interactor and substrate. PSD93, but not other MaGUKs, localizes to the Axon Initial Segment (AIS). Using lentiviral-mediated shRNA knockdown in rat hippocampal neurons, we find that ZDHHC14 controls palmitoylation and AIS clustering of PSD93 and also of Kv1 potassium channels, which directly bind PSD93. Neurodevelopmental expression of ZDHHC14 mirrors that of PSD93 and Kv1 channels and, consistent with ZDHHC14’s importance for Kv1 channel clustering, loss of ZDHHC14 decreases outward currents and increases action potential firing in hippocampal neurons. To our knowledge, these findings identify the first neuronal roles and substrates for ZDHHC14 and reveal a previously unappreciated role for palmitoylation in control of neuronal excitability.Impact StatementZDHHC14 controls palmitoylation and axon initial segment targeting of PSD93 and Kv1-family potassium channels, events that are essential for normal neuronal excitability.

scholarly journals Artemisinin-treatment in pre-symptomatic APP-PS1 mice increases gephyrin phosphorylation at Ser270: a modification regulating postsynaptic GABAAR density

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Eva Kiss ◽  
Stefan Kins ◽  
Karin Gorgas ◽  
Maret Orlik ◽  
Carolin Fischer ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Sesquiterpene Lactones ◽  
Phosphorylation Sites ◽  
Additional Increase ◽  
Antimalarial Agents ◽  
Gabaergic Synapses ◽  
Protein Density ◽  
Activity Dependent ◽  
The Brain

Abstract Artemisinins, a group of plant-derived sesquiterpene lactones, are efficient antimalarial agents. They also share anti-inflammatory and anti-viral activities and were considered for treatment of neurodegenerative disorders like Alzheimer’s disease (AD). Additionally, artemisinins bind to gephyrin, the multifunctional scaffold of GABAergic synapses, and modulate inhibitory neurotransmission in vitro. We previously reported an increased expression of gephyrin and GABAA receptors in early pre-symptomatic stages of an AD mouse model (APP-PS1) and in parallel enhanced CDK5-dependent phosphorylation of gephyrin at S270. Here, we studied the effects of artemisinin on gephyrin in the brain of young APP-PS1 mice. We detected an additional increase of gephyrin protein level, elevated gephyrin phosphorylation at Ser270, and an increased amount of GABAAR-γ2 subunits after artemisinin-treatment. Interestingly, the CDK5 activator p35 was also upregulated. Moreover, we demonstrate decreased density of postsynaptic gephyrin and GABAAR-γ2 immunoreactivities in cultured hippocampal neurons expressing gephyrin with alanine mutations at two CDK5 phosphorylation sites. In addition, the activity-dependent modulation of synaptic protein density was abolished in neurons expressing gephyrin lacking one or both of these phosphorylation sites. Thus, our results reveal that artemisinin modulates expression as well as phosphorylation of gephyrin at sites that might have important impact on GABAergic synapses in AD.

scholarly journals Thyroid Hormone (T3)-Induced Up-Regulation of Voltage-Activated Sodium Current in Cultured Postnatal Hippocampal Neurons Requires Secretion of Soluble Factors from Glial Cells

2009 ◽  
Vol 23 (9) ◽  
pp. 1494-1504 ◽  
Author(s):  
Vanessa Niederkinkhaus ◽  
Romy Marx ◽  
Gerd Hoffmann ◽  
Irmgard D. Dietzel
Keyword(s):  
Thyroid Hormone ◽  
Glial Cells ◽  
Current Density ◽  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Sodium Current ◽  
Na Current ◽  
Soluble Factors ◽  
Voltage Gated ◽  
Postnatal Rats

Abstract We have previously shown that treatment with the thyroid hormone T3 increases the voltage-gated Na+current density (Nav-D) in hippocampal neurons from postnatal rats, leading to accelerated action potential upstrokes and increased firing frequencies. Here we show that the Na+ current regulation depends on the presence of glial cells, which secrete a heat-instable soluble factor upon stimulation with T3. The effect of conditioned medium from T3-treated glial cells was mimicked by basic fibroblast growth factor (bFGF), known to be released from cerebellar glial cells after T3 treatment. Neutralization assays of astrocyte-conditioned media with anti-bFGF antibody inhibited the regulation of the Nav-D by T3. This suggests that the up-regulation of the neuronal sodium current density by T3 is not a direct effect but involves bFGF release and satellite cells. Thus glial cells can modulate neuronal excitability via secretion of paracrinely acting factors.

scholarly journals Ps in the (Channel) Pod Are Not Alike …

2007 ◽  
Vol 7 (5) ◽  
pp. 136-137
Author(s):  
Yoav Noam ◽  
Tallie Z. Baram
Keyword(s):  
Neuronal Activity ◽  
Hippocampal Neurons ◽  
Neuronal Excitability ◽  
Phosphorylation Sites ◽  
Voltage Dependent ◽  
Activity Dependent ◽  
Stimulation Of ◽  
Cultured Hippocampal Neurons

Bidirectional Activity-Dependent Regulation of Neuronal Ion Channel Phosphorylation. Misonou H, Menegola M, Mohapatra DP, Guy LK, Park KS, Trimmer JS. J Neurosci 2006;26(52):13505–13514. Activity-dependent dephosphorylation of neuronal Kv2.1 channels yields hyperpolarizing shifts in their voltage-dependent activation and homoeostatic suppression of neuronal excitability. We recently identified 16 phosphorylation sites that modulate Kv2.1 function. Here, we show that in mammalian neurons, compared with other regulated sites, such as serine (S)563, phosphorylation at S603 is supersensitive to calcineurin-mediated dephosphorylation in response to kainate-induced seizures in vivo, and brief glutamate stimulation of cultured hippocampal neurons. In vitro calcineurin digestion shows that supersensitivity of S603 dephosphorylation is an inherent property of Kv2.1. Conversely, suppression of neuronal activity by anesthetic in vivo causes hyperphosphorylation at S603 but not S563. Distinct regulation of individual phosphorylation sites allows for graded and bidirectional homeostatic regulation of Kv2.1 function. S603 phosphorylation represents a sensitive bidirectional biosensor of neuronal activity.

scholarly journals Severe deficiency of voltage-gated sodium channel NaV1.2 elevates neuronal excitability in adult mice

2021 ◽  
Author(s):  
Jingliang Zhang ◽  
Xiaoling Chen ◽  
Muriel Eaton ◽  
Shirong Lai ◽  
Anthony Park ◽  
...  
Keyword(s):  
Potassium Channels ◽  
Sodium Channel ◽  
Neuronal Excitability ◽  
Brain Slices ◽  
List Type ◽  
Voltage Gated Sodium Channel ◽  
Neuronal Hyperexcitability ◽  
Voltage Gated ◽  
Adult Mice ◽  
Mechanistic Investigation

AbstractScn2a encodes voltage-gated sodium channel NaV1.2, which mediates neuronal firing. The current paradigm suggests that NaV1.2 gain-of-function variants enhance neuronal excitability resulting in epilepsy, whereas NaV1.2 deficiency impairs neuronal excitability contributing to autism. In this paradigm, however, why about a third of patients with NaV1.2 deficiency still develop seizures remains a mystery. Here we challenge the conventional wisdom, reporting that neuronal excitability is increased with severe NaV1.2 deficiency. Using a unique gene-trap knockout mouse model of Scn2a, we found enhanced intrinsic excitabilities of principal neurons in the cortico-striatal circuit, known to be involved in Scn2a-related seizures. This increased excitability is autonomous, and is reversible by genetic restoration of Scn2a expression in adult mice. Mechanistic investigation reveals a compensatory downregulation of potassium channels including KV1.1, which could be targeted to alleviate neuronal hyperexcitability. Our unexpected findings may explain NaV1.2 deficiency-related epileptic seizures in humans and provide molecular targets for potential interventions.TEASERSevere NaV1.2 deficiency results in neuronal hyperexcitability via the compensatory downregulation of potassium channels.HIGHLIGHTSSevere NaV1.2 deficiency results in enhanced excitability of medium spiny neurons (MSNs) and pyramidal neurons in adult mice;Increased neuronal excitability in MSNs is accompanied by elevated voltage threshold;NaV1.2 deficiency-related hyperexcitability is reversible with the restoration of Scn2a expression, and is autonomous;The expression of the KV1.1 channel has a compensatory reduction in neurons with NaV1.2 deficiency, and KV channels openers normalize the neuronal excitability;The enhanced excitability in brain slices translates to elevated in vivo firing commonly associated with seizures.

scholarly journals Voltage-gated potassium channels ensure action potential shape fidelity in distal axons

2020 ◽  
Author(s):  
Victoria Gonzalez Sabater ◽  
Mark Rigby ◽  
Juan Burrone
Keyword(s):  
Potassium Channels ◽  
Action Potential ◽  
Hippocampal Neurons ◽  
Digital Signal ◽  
Voltage Gated ◽  
Kv Channel ◽  
Potential Shape ◽  
Blocking Voltage ◽  
Presynaptic Boutons ◽  
Action Potential Shape

The initiation and propagation of the action potential (AP) along an axon allows neurons to convey information rapidly and across distant sites. Although AP properties have typically been characterised at the soma and proximal axon, the propagation of APs towards distal axonal domains of mammalian neurons remains limited. We used Genetically Encoded Voltage Indicators (GEVIs) to image APs simultaneously at different locations along the long axons of dissociated hippocampal neurons with sub-millisecond temporal resolution. We found that APs became sharper and showed remarkable fidelity as they traveled towards distal axons, even during a high frequency train. Blocking voltage-gated potassium channels (Kv) with 4-AP resulted in an increase in AP width in all compartments, which was stronger at distal locations and exacerbated during AP trains. We conclude that the higher levels of Kv channel activity in distal axons serves to sustain AP fidelity, conveying a reliable digital signal to presynaptic boutons.

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