The Role of Kv7/M Potassium Channels in Controlling Ectopic Firing in Nociceptors

Abstract

Peripheral nociceptive neurons encode and convey injury-inducing stimuli toward the central nervous system. In normal conditions, tight control of nociceptive resting potential prevents their spontaneous activation. However, in many pathological conditions the control of membrane potential is disrupted, leading to ectopic, stimulus-unrelated firing of nociceptive neurons, which is correlated to spontaneous pain. We have investigated the role of KV7/M channels in stabilizing membrane potential and impeding spontaneous firing of nociceptive neurons. These channels generate low voltage-activating, noninactivating M-type K+ currents (M-current, IM), which control neuronal excitability. Using perforated-patch recordings from cultured, rat nociceptor-like dorsal root ganglion neurons, we show that inhibition of M-current leads to depolarization of nociceptive neurons and generation of repetitive firing. To assess to what extent the M-current, acting at the nociceptive terminals, is able to stabilize terminals' membrane potential, thus preventing their ectopic activation, in normal and pathological conditions, we built a multi-compartment computational model of a pseudo-unipolar unmyelinated nociceptive neuron with a realistic terminal tree. The modeled terminal tree was based on the in vivo structure of nociceptive peripheral terminal, which we assessed by in vivo multiphoton imaging of GFP-expressing nociceptive neuronal terminals innervating mice hind paw. By modifying the conductance of the KV7/M channels at the modeled terminal tree (terminal gKV7/M) we have found that 40% of the terminal gKV7/M conductance is sufficient to prevent spontaneous firing, while ~75% of terminal gKV7/M is sufficient to inhibit stimulus induced activation of nociceptive neurons. Moreover, we showed that terminal M-current reduces susceptibility of nociceptive neurons to a small fluctuations of membrane potentials. Furthermore, we simulated how the interaction between terminal persistent sodium current and M-current affects the excitability of the neurons. We demonstrated that terminal M-current in nociceptive neurons impeded spontaneous firing even when terminal Na(V)1.9 channels conductance was substantially increased. On the other hand, when terminal gKV7/M was decreased, nociceptive neurons fire spontaneously after slight increase in terminal Na(V)1.9 conductance. Our results emphasize the pivotal role of M-current in stabilizing membrane potential and hereby in controlling nociceptive spontaneous firing, in normal and pathological conditions.

KCNQ/M-channels regulate mouse vagal bronchopulmonary C-fiber excitability and cough sensitivity

“…In fact, we found that XE991 caused a slight increase in AP threshold and had a tendency to reduce AP discharge at nodose C-fiber terminals in the lungs. These observations are at odds with the repetitive AP firing induced by focal puff application of XE991 in rat lumbar DRG neurons (51) and with the finding that XE991 modestly increased afferent firing in response to noxious bowel distension in mouse distal colons (17). However, the absence of effects on AP firing properties in mouse sympathetic neurons (52) and an increase in the pressure threshold for rat baroreceptor discharge (16) by XE991 have also been reported.…”

M‐type K+ channels in peripheral nociceptive pathways

“…A recent computational study provided a biophysical foundation to these and similar observations by utilizing a multi‐component model of rat C fibre that included a geometrically realistic nociceptive nerve ending in the skin (Barkai et al, ). When sufficiently pronounced, M channel inhibition resulted in ‘spontaneous firing’.…”

The input-output relation of primary nociceptive neurons is determined by the morphology of the peripheral nociceptive terminals

“…For the "realistic" type of the terminal tree, which was reconstructed according to one of our arbitrary experimental observations (Barkai et al, 2017), the distal axon ending tapered at its end and expanded into a terminal tree composed of 27 branches. For proper electrical propagation from the terminal tree to the peripheral axon, these two compartments were connected by a tapered cone-like axon with a linearly changing diameter over 100 µm of length.…”

“…The model neuron of all tree structures includes the following Hodgkin-Huxley-type ion channels used in Barkai et al (Barkai et al, 2017) and Goldstein et al (Goldstein et al, 2019):…”

“…A capsaicin-like induced current was introduced into a single simplified voltage-clamp point-process with fast exponential activation and slow exponential inactivation mimicking the experimental kinetics of puff-applied 1 μM capsaicin-induced current and sufficient to induce action potential firing when applied onto the acutely dissociated dorsal root ganglion neuron (Nita et al, 2016). The similar current was used in Barkai et al (Barkai et al, 2017) and Goldstein et al (Goldstein et al, 2019) to generate activity in the modeled nociceptive neuron when applied to the single 75 m length terminal:…”