Timing is everything: structural insights into the disease-linked Kv3 channels controlling fast action-potential firing in the brain

Gunthorpe, Martin J.

doi:10.1038/s41467-022-31537-4

Cited by 7 publications

(5 citation statements)

References 23 publications

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“…In humans, >70 Kv channels are encoded in their genome and they are crucial for maintaining the electrical excitability of cells and also involved in chemical signalling ( Gunthrope, 2022 ). Even subtle mutations in them leads to drastic changes in their functional behaviour and underlie many genetically-inherited pathological conditions ( Catterall, 2010 ).…”

Section: Discussionmentioning

confidence: 99%

Cholesterol modulates the structural dynamics of the paddle motif loop of KvAP voltage sensor

Das,

Bysack,

Raghuraman

2024

Current Research in Structural Biology

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Section: Discussionmentioning

confidence: 99%

Cholesterol modulates the structural dynamics of the paddle motif loop of KvAP voltage sensor

Das,

Bysack,

Raghuraman

2024

Current Research in Structural Biology

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“…Interestingly, Kv3.3 mRNA and proteins are expressed in midbrain neurons [ 73 , 74 ]. They belong to the family of Kv3 channels, which open only during action potentials, contributing to fast repolarization [ 75 ] and energy-efficient firing [ 76 ]. GluR2 ( Gria2 gene) constituting AMPAR was co-purified with HCN2 channel subunits.…”

Section: Discussionmentioning

confidence: 99%

High-Resolution Proteomics Unravel a Native Functional Complex of Cav1.3, SK3, and Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels in Midbrain Dopaminergic Neurons

Belghazi,

Iborra,

Toutendji

et al. 2024

Cells

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Pacemaking activity in substantia nigra dopaminergic neurons is generated by the coordinated activity of a variety of distinct somatodendritic voltage- and calcium-gated ion channels. We investigated whether these functional interactions could arise from a common localization in macromolecular complexes where physical proximity would allow for efficient interaction and co-regulations. For that purpose, we immunopurified six ion channel proteins involved in substantia nigra neuron autonomous firing to identify their molecular interactions. The ion channels chosen as bait were Cav1.2, Cav1.3, HCN2, HCN4, Kv4.3, and SK3 channel proteins, and the methods chosen to determine interactions were co-immunoprecipitation analyzed through immunoblot and mass spectrometry as well as proximity ligation assay. A macromolecular complex composed of Cav1.3, HCN, and SK3 channels was unraveled. In addition, novel potential interactions between SK3 channels and sclerosis tuberous complex (Tsc) proteins, inhibitors of mTOR, and between HCN4 channels and the pro-degenerative protein Sarm1 were uncovered. In order to demonstrate the presence of these molecular interactions in situ, we used proximity ligation assay (PLA) imaging on midbrain slices containing the substantia nigra, and we could ascertain the presence of these protein complexes specifically in substantia nigra dopaminergic neurons. Based on the complementary functional role of the ion channels in the macromolecular complex identified, these results suggest that such tight interactions could partly underly the robustness of pacemaking in dopaminergic neurons.

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“…They proposed targeting alterations in biophysical ion channels as a potential strategy in the design of future therapies to ameliorate cortical circuit hyperexcitability in early AD. Human genetic studies have identified mutations in three out of the four subtypes of Kv3 channels as causal mutations linking Kv3 channel dysfunction to brain disorders [149]. Andrade-Talavera et al [150] were able to modulate Kv3.1 and Kv3.2 electrophysiologically to rescue Aβ-induced desynchronization of fastspiking interneuron firing in an in vitro AD model and thus restore gamma oscillations.…”

Section: Molecular Mechanisms Underlying Pv+ Interneuron Dysfunction ...mentioning

confidence: 99%

Parvalbumin Interneuron Dysfunction in Neurological Disorders: Focus on Epilepsy and Alzheimer’s Disease

Leitch

2024

IJMS

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Parvalbumin expressing (PV+) GABAergic interneurons are fast spiking neurons that provide powerful but relatively short-lived inhibition to principal excitatory cells in the brain. They play a vital role in feedforward and feedback synaptic inhibition, preventing run away excitation in neural networks. Hence, their dysfunction can lead to hyperexcitability and increased susceptibility to seizures. PV+ interneurons are also key players in generating gamma oscillations, which are synchronized neural oscillations associated with various cognitive functions. PV+ interneuron are particularly vulnerable to aging and their degeneration has been associated with cognitive decline and memory impairment in dementia and Alzheimer’s disease (AD). Overall, dysfunction of PV+ interneurons disrupts the normal excitatory/inhibitory balance within specific neurocircuits in the brain and thus has been linked to a wide range of neurodevelopmental and neuropsychiatric disorders. This review focuses on the role of dysfunctional PV+ inhibitory interneurons in the generation of epileptic seizures and cognitive impairment and their potential as targets in the design of future therapeutic strategies to treat these disorders. Recent research using cutting-edge optogenetic and chemogenetic technologies has demonstrated that they can be selectively manipulated to control seizures and restore the balance of neural activity in the brains of animal models. This suggests that PV+ interneurons could be important targets in developing future treatments for patients with epilepsy and comorbid disorders, such as AD, where seizures and cognitive decline are directly linked to specific PV+ interneuron deficits.

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Timing is everything: structural insights into the disease-linked Kv3 channels controlling fast action-potential firing in the brain

Cited by 7 publications

References 23 publications

Cholesterol modulates the structural dynamics of the paddle motif loop of KvAP voltage sensor

Cholesterol modulates the structural dynamics of the paddle motif loop of KvAP voltage sensor

High-Resolution Proteomics Unravel a Native Functional Complex of Cav1.3, SK3, and Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels in Midbrain Dopaminergic Neurons

Parvalbumin Interneuron Dysfunction in Neurological Disorders: Focus on Epilepsy and Alzheimer’s Disease

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