Ion Channels under the Sun

Abbott, Geoffrey W.; Pitt, Geoffrey S.

doi:10.1096/fj.14-0501ufm

Cited by 7 publications

(6 citation statements)

References 63 publications

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“…In addition to whole cells, specific ion channels can also be used as transducers. Ion channels are involved in electrical signal conduction (such as in the nervous or cardiac systems) as well as in other disease areas such as oncology, 280 cystic fibrosis, 281 diabetes, 282 and infection. 283 The gold standard for monitoring ion channel currents is the patch clamp technique, 284 which provides highly accurate functional recordings from single or multiple ion channels in cells.…”

Section: Laboratory-based Diagnosis (“High-throughput Screening”)mentioning

confidence: 99%

Diverse Applications of Nanomedicine

Pelaz¹,

et al. 2017

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The design and use of materials in the nanoscale size range for addressing medical and health-related issues continues to receive increasing interest. Research in nanomedicine spans a multitude of areas, including drug delivery, vaccine development, antibacterial, diagnosis and imaging tools, wearable devices, implants, high-throughput screening platforms, etc. using biological, nonbiological, biomimetic, or hybrid materials. Many of these developments are starting to be translated into viable clinical products. Here, we provide an overview of recent developments in nanomedicine and highlight the current challenges and upcoming opportunities for the field and translation to the clinic.

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Section: Laboratory-based Diagnosis (“High-throughput Screening”)mentioning

confidence: 99%

Diverse Applications of Nanomedicine

Pelaz¹,

et al. 2017

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“…Voltage-gated K + (Kv) channels play a crucial role in regulating excitability, and dysregulation of their function has been associated with several disorders, including cardiac arrhythmias, epilepsy, and autism. Kv channels, including all members of the Kv7 family (Kv7.1–Kv7.5, also known as KCNQ as they are encoded by KCNQ1–5 genes; Jespersen et al, 2005 ; Jentsch, 2000 ; Abbott and Pitt, 2014 ), are highly heterogenous and widely expressed in excitable cells where they regulate resting membrane potential, shape the firing and duration of action potentials, and control rhythmic events ( Hille, 2001 ).…”

Section: Introductionmentioning

confidence: 99%

Distinctive mechanisms of epilepsy-causing mutants discovered by measuring S4 movement in KCNQ2 channels

Edmond

Hinojo-Perez

et al. 2022

eLife

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Neuronal KCNQ channels mediate the M-current, a key regulator of membrane excitability in the central and peripheral nervous systems. Mutations in KCNQ2 channels cause severe neurodevelopmental disorders, including epileptic encephalopathies. However, the impact that different mutations have on channel function remains poorly defined, largely because of our limited understanding of the voltage sensing mechanisms that trigger channel gating. Here, we define parameters of voltage sensor movements in wt-KCNQ2 and channels bearing epilepsy-associated mutations using cysteine accessibility and voltage clamp fluorometry (VCF). Cysteine modification reveals that a stretch of 8-9 amino acids in the S4 become exposed upon VSD activation of KCNQ2 channels. VCF shows that the voltage dependence and the time course of S4 movement and channel opening/closing closely correlate. VCF reveals different mechanisms by which different epilepsy-associated mutations affect KCNQ2 channel voltage-dependent gating. This study provides insight into KCNQ2 channel function, which will aid in uncovering the mechanisms underlying channelopathies.

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“…Kv channels are widely expressed in the peripheral and central neurons, where they help to regulate resting membrane potential, action potential shape and frequency, and neurotransmitter release 1 . Members of the Kv7 family of channels (Kv7.2, Kv7.3, and Kv7.5; also known as KCNQ channels 2, 3, 4 ) are found in axon initial segments and Nodes of Ranvier of multiple neuronal types, where they play a critical role in generating the sub-threshold K + current (M-current) that regulates excitability 5, 6 . The slow activation of KCNQ channels during action potential initiation and their lack of inactivation leads to sustained outward K + currents that promote the restoration of resting membrane potential during repetitive firing.…”

Section: Introductionmentioning

confidence: 99%

Lipophilic compounds restore wt function of neurodevelopmental-associated KCNQ3 mutations

Edmond,

Hinojo-Perez,

Efrem

et al. 2024

Preprint

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A major driver of neuronal hyperexcitability is dysfunction of K+channels, including voltage-gated KCNQ2/3 channels. Their slow activation and deactivation kinetics produces a current that regulates membrane potential and impedes repetitive firing. Mutations in KCNQ2 and KCNQ3 lead to a wide spectrum of neurodevelopmental disorders (NDDs), ranging from benign familial neonatal seizures to severe epileptic encephalopathies and autism spectrum disorders. However, the impact of these mutations on KCNQ channel function remains poorly understood and existing treatments have unpleasant side effects. Here we use voltage clamp fluorometry and molecular dynamic simulations to investigate how R227Q and R236C, two novel NDD-causing mutations in the voltage sensor of KCNQ3, impair channel function. We show that the two mutations perturb channel gating by two distinct mechanisms: R227Q altering voltage sensor movement and R236C altering voltage sensor-to-gate coupling. Our study further shows that polyunsaturated fatty acids (PUFAs), a novel class of ion channel modulators, primarily target the voltage sensor domain in its activated conformation and yield partial and complete restoration of wt function in R227Q– and R236C-containing channels, respectively. Our results reveal the potential of PUFAs to be developed into therapies for diverse KCNQ3-based channelopathies.

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Ion Channels under the Sun

Cited by 7 publications

References 63 publications

Diverse Applications of Nanomedicine

Diverse Applications of Nanomedicine

Distinctive mechanisms of epilepsy-causing mutants discovered by measuring S4 movement in KCNQ2 channels

Lipophilic compounds restore wt function of neurodevelopmental-associated KCNQ3 mutations

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