Tinnitus and the potassium channels activity (papers by Dr Tzounopoulos)

[pattismith]

(Dr. Tzounopoulos, who is associate professor of otolaryngology and neurobiology at the University of Pittsburgh)

Noise-Induced Plasticity of KCNQ2/3 and HCN Channels

Underlies Vulnerability and Resilience to Tinnitus
Vulnerability to noise-induced tinnitus is associated with increased spontaneous firing rate in dorsal cochlear nucleus principal neurons, fusiform cells.

This hyperactivity is caused, at least in part, by decreased Kv7.2/3 (KCNQ2/3) potassium currents.

However, the biophysical mechanisms underlying resilience to tinnitus, which is observed in noise- exposed mice that do not develop tinnitus (non-tinnitus mice), remain unknown. Our results show that noise exposure induces, on average, a reduction in KCNQ2/3 channel activity in DCN fusiform cells in noise-exposed mice by 4 days after exposure. Tinnitus is developed in mice that do not compensate for this reduction within the next 3 days.
Resilience to tinnitus is developed in mice that show a re-emergence of KCNQ2/3 channel activity and a reduction in HCN channel activity.

Our results highlight KCNQ2/3 and HCN channels as potential targets for designing novel therapeutics that may promote resilience to tinnitus.
http://www.jneurosci.org/content/35/23/8829.short
Potent KCNQ2/3-Specific Channel Activator Suppresses In Vivo Epileptic Activity and Prevents the Development of Tinnitus


Abstract
Voltage-gated Kv7 (KCNQ) channels are voltage-dependent potassium channels that are activated at resting membrane potentials and therefore provide a powerful brake on neuronal excitability.

Genetic or experience-dependent reduction of KCNQ2/3 channel activity is linked with disorders that are characterized by neuronal hyperexcitability, such as epilepsy and tinnitus.

Retigabine, a small molecule that activates KCNQ2–5 channels by shifting their voltage-dependent opening to more negative voltages, is an US Food and Drug Administration (FDA) approved anti-epileptic drug.

However, recently identified side effects have limited its clinical use. As a result, the development of improved KCNQ2/3 channel activators is crucial for the treatment of hyperexcitability-related disorders.
By incorporating a fluorine substituent in the 3-position of the tri-aminophenyl ring of retigabine, we synthesized a small-molecule activator (SF0034) with novel properties.
Heterologous expression of KCNQ2/3 channels in HEK293T cells showed that SF0034 was five times more potent than retigabine at shifting the voltage dependence of KCNQ2/3 channels to more negative voltages.
Moreover, unlike retigabine, SF0034 did not shift the voltage dependence of either KCNQ4 or KCNQ5 homomeric channels.
Conditional deletion of Kcnq2 from cerebral cortical pyramidal neurons showed that SF0034 requires the expression of KCNQ2/3 channels for reducing the excitability of CA1 hippocampal neurons. Behavioral studies demonstrated that SF0034 was a more potent and less toxic anticonvulsant than retigabine in rodents. Furthermore, SF0034 prevented the development of tinnitus in mice. We propose that SF0034 provides, not only a powerful tool for investigating ion channel properties, but, most importantly, it provides a clinical candidate for treating epilepsy and preventing tinnitus.

 

[ahmo]

I had horrific tinnitus. It lessened when I quit gluten and dairy, and essentially disappeared when my adrenals were less stressed.

 

[Sundancer]

I had terrible tinnitus too, as with Ahmo, it lessened when I stopped dairy ( I've been gluten-low for decennia, so that little that I stopped hardly counts)
Used theanine and DPPIV and after some weeks the tinnitus vanished.

I now found that histamine triggers the reoccurence...

At the moment I'm on a mix of injected hydroxycobalamine, a small amount of antihistamine and potassium. Feel enormously better.

But now searching for the how and why of potassium supplementation, I realize now that years before I fell sick I had the signs that I now interpret as : take a mug of potassium and you'll feel better.

 

[percyval577]

Genetic or experience-dependent reduction of KCNQ2/3 channel activity is linked with disorders that are characterized by neuronal hyperexcitability, such as epilepsy and tinnitus.

My tinnitus can be quite loud (but I don´t give any attention to it, it´s only a noise, constant in the range of hours, I am really used to it). I have it since EBV, it lessend and vanished in between for some years, due to diet obviously (low manganese).

I too benefit from potassium intake (@Sundancer ), the effect though is not too strong.

Potassium is interesting because it is a regulation of excitabillity by ions that come firstly out of the cell (instead of firstly coming in like the other three ions). Here another article with the same goal, adding nitric oxide.

Steinert, Robinson 2011 Abstract

Activity-dependent changes in synaptic strength are well established as mediating long-term plasticity underlying learning and memory, but modulation of target neuron excitability could complement changes in synaptic strength and regulate network activity. It is thought that homeostatic mechanisms match intrinsic excitability to the incoming synaptic drive, but evidence for involvement of voltage-gated conductances is sparse. Here, we show that glutamatergic synaptic activity modulates target neuron excitability and switches the basis of action potential repolarization from Kv3 to Kv2 potassium channel dominance, thereby adjusting neuronal signaling between low and high activity states, respectively. This nitric oxide-mediated signaling dramatically increases Kv2 currents in both the auditory brain stem and hippocampus (>3-fold) transforming synaptic integration and information transmission but with only modest changes in action potential waveform. We conclude that nitric oxide is a homeostatic regulator, tuning neuronal excitability to the recent history of excitatory synaptic inputs over intervals of minutes to hours.

I guess though it´s all over the brain comparable enough.

For KCNQ2 and KCNQ3 another terminolgy is: Kv7.2 and Kv7.3).

This quoted sequence I think might easlily be one parameter for coming out of our disease,
going potentially along with the experience of PEM.


You have interesting stuff on the cards @pattismith.