Phosphoinositide Modulation of Heteromeric Kv1 Channels Adjusts Output of Spiral Ganglion Neurons from Hearing Mice

Smith, Katie E.; Browne, Lorcan; Selwood, David L.; McAlpine, David; Jagger, Daniel J.

doi:10.1523/jneurosci.0496-15.2015

Cited by 32 publications

(58 citation statements)

References 59 publications

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“…A number of earlier studies have reported a significant increase in firing output following application of dendrotoxin, increasing the firing rate of both rapidly-adapting and slowly-adapting neurons in its presence37394142. That result implicated K V 1.1 and K V 1.2 in the control of firing frequency.…”

Section: Discussionmentioning

confidence: 89%

Firing frequency and entrainment maintained in primary auditory neurons in the presence of combined BDNF and NT3

Wright

Gillespie

O’Leary

et al. 2016

Sci Rep

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Primary auditory neurons rely on neurotrophic factors for development and survival. We previously determined that exposure to brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT3) alters the activity of hyperpolarization-activated currents (Ih) in this neuronal population. Since potassium channels are sensitive to neurotrophins, and changes in Ih are often accompanied by a shift in voltage-gated potassium currents (IK), this study examined IK with exposure to both BDNF and NT3 and the impact on firing entrainment during high frequency pulse trains. Whole-cell patch-clamp recordings revealed significant changes in action potential latency and duration, but no change in firing adaptation or total outward IK. Dendrotoxin-I (DTX-I), targeting voltage-gated potassium channel subunits KV1.1 and KV1.2, uncovered an increase in the contribution of DTX-I sensitive currents with exposure to neurotrophins. No difference in Phrixotoxin-1 (PaTX-1) sensitive currents, mediated by KV4.2 and KV4.3 subunits, was observed. Further, no difference was seen in firing entrainment. These results show that combined BDNF and NT3 exposure influences the contribution of KV1.1 and KV1.2 to the low voltage-activated potassium current (IKL). Whilst this is accompanied by a shift in spike latency and duration, both firing frequency and entrainment to high frequency pulse trains are preserved.

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Section: Discussionmentioning

confidence: 89%

Firing frequency and entrainment maintained in primary auditory neurons in the presence of combined BDNF and NT3

Wright

Gillespie

O’Leary

et al. 2016

Sci Rep

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“…Based on this, one could speculate that ramped pulses excite sites on the auditory nerve fiber distinct from rectangular pulses to produce steeper growth function. Interestingly, immunostainings show that Kv.1.1and Kv1.2 subunits of the ramp-sensitive KLT channels localize to SGN somata 7 , but whether there is a relation between ramped stimulation, KLT localization and site of excitation has yet to be determined. Indeed, it would be interesting to explore how and at which site ramped and rectangular pulses excite the auditory nerve fibers, using latency data from single-or multiunit neuronal recordings.…”

Section: Discussionmentioning

confidence: 99%

“…First, ramped pulses reportedly match ion channel dynamics of SGN better 4 . SGNs, among other neurons in the auditory system, express low-threshold potassium channels (KLT) 7 . These ion channels are sensitive to the rate of change of a synaptic input current and regulate firing patterns, in particular adaptation to high stimulation rate, by extending the refractory period and a sharp timing of the action potential [7][8][9][10][11] .…”

mentioning

confidence: 99%

“…SGNs, among other neurons in the auditory system, express low-threshold potassium channels (KLT) 7 . These ion channels are sensitive to the rate of change of a synaptic input current and regulate firing patterns, in particular adaptation to high stimulation rate, by extending the refractory period and a sharp timing of the action potential [7][8][9][10][11] . For example, in patch clamp recordings on cultured SGNs, Ballestro et al showed that the stimulus efficiency needed to evoke action potentials increased as the stimulus slope became steeper 4 .…”

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confidence: 99%

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Ramped pulse shapes are more efficient for cochlear implant stimulation in an animal model

Navntoft

Marozeau

Barkat

2020

Sci Rep

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In all commercial cochlear implant (CI) devices, the electric stimulation is performed with a rectangular pulse that generally has two phases of opposite polarity. To date, developing new stimulation strategies has relied on the efficacy of this shape. Here, we investigate the potential of a novel stimulation paradigm that uses biophysically-inspired electrical ramped pulses. Using electrically-evoked auditory brainstem response (eABR) recordings in mice, we found that less charge, but higher current level amplitude, is needed to evoke responses with ramped shapes that are similar in amplitude to responses obtained with rectangular shapes. The most charge-efficient pulse shape had a rising ramp over both phases, supporting findings from previous in vitro studies. This was also true for longer phase durations. Our study presents the first physiological data on CI-stimulation with ramped pulse shapes. By reducing charge consumption ramped pulses have the potential to produce more battery-efficient CIs and may open new perspectives for designing other efficient neural implants in the future.

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“…We blocked these steps with three chemical tools: neomycin and an anti-PIP 2 antibody, which block the access of PLC to PIP 2 ; and the non-hydrolysable PIP 2 analogue diC8-PIP 2 , a putative competitive inhibitor of phospholipases [25][26][27][28]. The presence of each of the inhibitors prevented the PE-induced shift in I hERG activation half voltage (Fig.…”

Section: Intracellular Pathway Mediating the α1-ar Modulation Of Hergmentioning

confidence: 99%

Mechanisms of IhERG/IKr Modulation by α1-Adrenoceptors in HEK293 Cells and Cardiac Myocytes

Urrutia

Alday

Gallego

et al. 2016

Cell Physiol Biochem

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Background: The rapid delayed rectifier K⁺ current (I_Kr), carried by the hERG protein, is one of the main repolarising currents in the human heart and a reduction of this current increases the risk of ventricular fibrillation. α1-adrenoceptors (α1-AR) activation reduces I_Kr but, despite the clear relationship between an increase in the sympathetic tone and arrhythmias, the mechanisms underlying the α1-AR regulation of the hERG channel are controversial. Thus, we aimed to investigate the mechanisms by which α1-AR stimulation regulates I_Kr. Methods: α1-adrenoceptors, hERG channels, auxiliary subunits minK and MIRP1, the non PIP₂-interacting mutant D-hERG (with a deletion of the 883-894 amino acids) in the C-terminal and the non PKC-phosphorylable mutant N-terminal truncated-hERG (NTK-hERG) were transfected in HEK293 cells. Cell membranes were extracted by centrifugation and the different proteins were visualized by Western blot. Potassium currents were recorded by the patch-clamp technique. I_Kr was recorded in isolated feline cardiac myocytes. Results: Activation of the α1-AR reduces the amplitude of I_hERG and I_Kr through a positive shift in the activation half voltage, which reduces the channel availability at physiological membrane potentials. The intracellular pathway connecting the α1-AR to the hERG channel in HEK293 cells includes activation of the Gαq protein, PLC activation and PIP₂ hydrolysis, activation of PKC and direct phosphorylation of the hERG channel N-terminal. The PKC-mediated I_Kr channel phosphorylation and subsequent I_Kr reduction after α1-AR stimulation was corroborated in feline cardiac myocytes. Conclusions: These findings clarify the link between sympathetic nervous system hyperactivity and I_Kr reduction, one of the best characterized causes of torsades de pointes and ventricular fibrillation.

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Phosphoinositide Modulation of Heteromeric Kv1 Channels Adjusts Output of Spiral Ganglion Neurons from Hearing Mice

Cited by 32 publications

References 59 publications

Firing frequency and entrainment maintained in primary auditory neurons in the presence of combined BDNF and NT3

Firing frequency and entrainment maintained in primary auditory neurons in the presence of combined BDNF and NT3

Ramped pulse shapes are more efficient for cochlear implant stimulation in an animal model

Mechanisms of IhERG/IKr Modulation by α1-Adrenoceptors in HEK293 Cells and Cardiac Myocytes

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