scholarly journals Truncating tau reveals different pathophysiological actions of oligomers in single neurons

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Emily Hill ◽  
Thomas K. Karikari ◽  
Juan Lantero-Rodriguez ◽  
Henrik Zetterberg ◽  
Kaj Blennow ◽  
...  
Keyword(s):  
Amino Acids ◽  
Action Potential ◽  
Sodium Channel ◽  
Tau Protein ◽  
Full Length ◽  
Single Neurons ◽  
Neuronal Function ◽  
Neuronal Structure ◽  
Voltage Gated ◽  
Specific Effects

AbstractTau protein is involved in maintaining neuronal structure. In Alzheimer’s disease, small numbers of tau molecules can aggregate to form oligomers. However, how these oligomers produce changes in neuronal function remains unclear. Previously, oligomers made from full-length human tau were found to have multiple effects on neuronal properties. Here we have cut the tau molecule into two parts: the first 123 amino acids and the remaining 124-441 amino acids. These truncated tau molecules had specific effects on neuronal properties, allowing us to assign the actions of full-length tau to different regions of the molecule. We identified one key target for the effects of tau, the voltage gated sodium channel, which could account for the effects of tau on the action potential. By truncating the tau molecule, we have probed the mechanisms that underlie tau dysfunction, and this increased understanding of tau’s pathological actions will build towards developing future tau-targeting therapies.

Increased Neuronal Firing in Computer Simulations of Sodium Channel Mutations That Cause Generalized Epilepsy With Febrile Seizures Plus

2004 ◽  
Vol 91 (5) ◽  
pp. 2040-2050 ◽  
Author(s):  
Jay Spampanato ◽  
Ildiko Aradi ◽  
Ivan Soltesz ◽  
Alan L. Goldin
Keyword(s):  
Action Potential ◽  
Sodium Channel ◽  
Febrile Seizures ◽  
Neuronal Firing ◽  
Voltage Gated Sodium Channel ◽  
Single Action ◽  
Voltage Gated ◽  
Single Action Potential ◽  
Generalized Epilepsy ◽  
Febrile Seizures Plus

Generalized epilepsy with febrile seizures plus (GEFS+) is an autosomal dominant familial syndrome with a complex seizure phenotype. It is caused by mutations in one of 3 voltage-gated sodium channel subunit genes ( SCN1B, SCN1A, and SCN2A) and the GABAA receptor γ2 subunit gene ( GBRG2). The biophysical characterization of 3 mutations (T875M, W1204R, and R1648H) in SCN1A, the gene encoding the CNS voltage-gated sodium channel α subunit Nav1.1, demonstrated a variety of functional effects. The T875M mutation enhanced slow inactivation, the W1204R mutation shifted the voltage dependency of activation and inactivation in the negative direction, and the R1648H mutation accelerated recovery from inactivation. To determine how these changes affect neuronal firing, we used the NEURON simulation software to design a computational model based on the experimentally determined properties of each GEFS+ mutant sodium channel and a delayed rectifier potassium channel. The model predicted that W1204R decreased the threshold, T875M increased the threshold, and R1648H did not affect the threshold for firing a single action potential. Despite the different effects on the threshold for firing a single action potential, all of the mutations resulted in an increased propensity to fire repetitive action potentials. In addition, each mutation was capable of driving repetitive firing in a mixed population of mutant and wild-type channels, consistent with the dominant nature of these mutations. These results suggest a common physiological mechanism for epileptogenesis resulting from sodium channel mutations that cause GEFS+.

scholarly journals Valproic acid interactions with the NavMs voltage-gated sodium channel

2019 ◽  
Vol 116 (52) ◽  
pp. 26549-26554 ◽  
Author(s):  
Geancarlo Zanatta ◽  
Altin Sula ◽  
Andrew J. Miles ◽  
Leo C. T. Ng ◽  
Rubben Torella ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Sodium Channel ◽  
Sodium Channels ◽  
Anticonvulsant Drug ◽  
Drug Binding ◽  
Voltage Sensor ◽  
Full Length ◽  
Binding Studies ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels

Valproic acid (VPA) is an anticonvulsant drug that is also used to treat migraines and bipolar disorder. Its proposed biological targets include human voltage-gated sodium channels, among other membrane proteins. We used the prokaryotic NavMs sodium channel, which has been shown to be a good exemplar for drug binding to human sodium channels, to examine the structural and functional interactions of VPA. Thermal melt synchrotron radiation circular dichroism spectroscopic binding studies of the full-length NavMs channel (which includes both pore and voltage sensor domains), and a pore-only construct, undertaken in the presence and absence of VPA, indicated that the drug binds to and destabilizes the channel, but not the pore-only construct. This is in contrast to other antiepileptic compounds that have previously been shown to bind in the central hydrophobic core of the pore region of the channel, and that tend to increase the thermal stability of both pore-only constructs and full-length channels. Molecular docking studies also indicated that the VPA binding site is associated with the voltage sensor, rather than the hydrophobic cavity of the pore domain. Electrophysiological studies show that VPA influences the block and inactivation rates of the NavMs channel, although with lower efficacy than classical channel-blocking compounds. It thus appears that, while VPA is capable of binding to these voltage-gated sodium channels, it has a very different mode and site of action than other anticonvulsant compounds.

Evidence that the Drosophila olfactory mutant smellblind defines a novel class of sodium channel mutation.

Genetics ◽  
1994 ◽  
Vol 136 (3) ◽  
pp. 1087-1096 ◽  
Author(s):  
M Lilly ◽  
R Kreber ◽  
B Ganetzky ◽  
J R Carlson
Keyword(s):  
Action Potential ◽  
Sodium Channel ◽  
Genetic Map ◽  
Potential Temperature ◽  
Transcription Unit ◽  
Temperature Sensitive ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated ◽  
Channel Mutation ◽  
Sodium Channel Mutation

Abstract The smellblind (sbl) gene of Drosophila is associated with olfactory defects, and the paralytic (para) gene encodes a voltage-gated sodium channel. sbl and para have similar genetic map positions, many combinations of sbl and para mutations fail to complement, and two sbl mutations contain molecular lesions within the para transcription unit. sbl mutations also behave like para mutations in that they are enhanced by the mutation no action potential temperature-sensitive (mlenapts1). The simplest interpretation of these results is that sbl and para are the same gene. Two sbl mutations produce olfactory defects not characteristic of classic sodium channel mutations and do not show typical heat-sensitive paralysis, suggesting that these sbl mutants define a novel class of sodium channel mutation.

scholarly journals Kinetic and thermodynamic modeling of a voltage-gated sodium channel

2021 ◽  
Author(s):  
Mara Almog ◽  
Nurit Degani-Katzav ◽  
Alon Korngreen
Keyword(s):  
Action Potential ◽  
Ion Channel ◽  
Sodium Channel ◽  
Temperature Dependence ◽  
Cortical Neurons ◽  
Room Temperature ◽  
Pyramidal Neurons ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels

Like all biological and chemical reactions, ion channel kinetics are highly sensitive to changes in temperature. Therefore, it is prudent to investigate channel dynamics at physiological temperatures. However, most ion channel investigations are performed at room temperature due to practical considerations, such as recording stability and technical limitations. This problem is especially severe for the fast voltage-gated sodium channel, whose activation kinetics are faster than the time constant of the standard patch-clamp amplifier at physiological temperatures. Thus, biologically detailed simulations of the action potential generation evenly scale the kinetic models of voltage-gated channels acquired at room temperature. To quantitatively study voltage-gated sodium channels' temperature sensitivity, we recorded sodium currents from nucleated patches extracted from the rat's layer five neocortical pyramidal neurons at several temperatures from 13.5 to 30°C. We use these recordings to model the kinetics of the voltage-gated sodium channel as a function of temperature. We show that the temperature dependence of activation differs from that of inactivation. Furthermore, we show that the sustained current has a different temperature dependence than the fast current. Our kinetic and thermodynamic analysis of the current provided a numerical model spanning the entire temperature range. This model reproduced vital features of channel activation and inactivation. Furthermore, the model also reproduced action potential dependence on temperature. Thus, we provide an essential building block for the generation of biologically detailed models of cortical neurons.

scholarly journals Voltage-gated sodium channel isoform-specific effects of pompilidotoxins

FEBS Journal ◽  
2010 ◽  
Vol 277 (4) ◽  
pp. 918-930 ◽  
Author(s):  
Emanuele Schiavon ◽  
Marijke Stevens ◽  
André J. Zaharenko ◽  
Katsuhiro Konno ◽  
Jan Tytgat ◽  
...  
Keyword(s):  
Sodium Channel ◽  
Voltage Gated Sodium Channel ◽  
Voltage Gated ◽  
Specific Effects
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