Targeting Two-Pore-Domain Potassium Channels by Mechanical Stretch Instantaneously Modulates Action Potential Transmission in Mouse Sciatic Nerves

Abstract

Recent reports indicate dominant roles of TRAAK and TREK-1 channels, i.e., mechanosensitive two-pore-domain potassium channels (K2P) at the nodes of Ranvier for action potential repolarization in mammalian peripheral nerves. Functional changes in mammalian peripheral nerve conduction by mechanical stretch studied by recording compound action potentials lack the necessary resolution to detect subtle neuromodulatory effects on conduction velocity. In this study, we developed a novel in vitro approach that enables single-fiber recordings from individual mouse sciatic nerve axons while delivering computer-controlled stepped stretch to the sciatic nerve trunk. Axial stretch instantaneously increased the conduction delay in both myelinated A-fibers and unmyelinated C-fibers. Increases in conduction delay linearly correlated with increases in axial stretch ratio for both A-and C-fibers. The slope of the increase in conduction delay versus stretch ratio was steeper in C-fibers than in A-fibers. Moderate axial stretch (14−19% of in vitro length) reversibly blocked 37.5% of unmyelinated C-fibers but none of the eight myelinated A-fibers tested. Application of arachidonic acid, an agonist to TRAAK and TREK-1 to sciatic nerve trunk, blocks axonal transmission in both A-and C-fibers with delayed onset and prolonged block. Also, the application of an antagonist ruthenium red showed a tendency of suppressing the stretch-evoked increase in conduction delay. These results could draw focused research on pharmacological and mechanical activation of K2P channels as a novel neuromodulatory strategy to achieve peripheral nerve block.

Increase in conduction velocity in myelinated nerves due to stretch – An experimental verification

“…In the results section it was mentioned that the percentage change in NCV AE-BE that we found through our measurements was about 0.62% per unit percentage stretch of nerve which is more than 0.15% obtained by Liu et al (2021) , as obtained through our reanalysis above. This may be due to the fact that our experimental values were obtained for efferent Aα-fibres while those by Liu et al, was obtained for afferent Aβ-fibres.…”

“…Combining all the factors discussed above, the new mechanism proposed by Rabbani (2018) appears to be an important and plausible explanation of the observed increases in ulnar NCV under stretch. At this point the work presented by Liu et al (2021) is worth going into details as it presents a very carefully designed experimental work on individual afferent nerve axons of both myelinated A-fibres and unmyelinated C-fibres. This work was carried out in-vitro on dissected rat sciatic nerves, measuring conduction delays in single axons (as against whole nerve trunks by many other authors, which carry some uncertainties) due to different magnitudes of stretch.…”

“…Again, ion channels, particularly of the recently discovered mechanosensitive two-pore-domain potassium channels (K2P: TRAAK and TREK-1) that are found at the nodes in afferent fibres, are expected to increase conduction delay, eventually leading to conduction block ( Kanda et al, 2019 ; Liu et al, 2021 ; Schwarz, 2021 ). A recent experimental measurement by Kanda et al (2023) clearly showed that mechanical stretch decreases the resting potential (makes it more negative).…”

“…We have re-analyzed experimental data presented by Liu et al (2021) to show that the an immediate and significant increase in the CV of myelinated fibres may only be explained on the basis of the new mechanism put forward by Rabbani (2018) . It is to be noted that this explanation achieved a greater strength since the above experiments compared the measured values on both myelinated and unmyelinated nerve fibres (single axons) under exactly the same measurement conditions.…”

Axonal membrane stretch suppresses neuronal excitability by activating mechanosensitive K2P channels at the node of Ranvier

“…Liu et al recently developed an experimental technique to apply an axonal mechanical stretch to ex vivo sciatic nerve preparation. Using these methods, they demonstrated that mechanical nerve stretch instantaneously mediates conduction delay in A-fibers [ 10 ]. Although membrane mechanical stretch has been suggested to modulate AP conduction, it is still unknown how membrane stretching modulates the excitability of axonal membranes at the NRs.…”