Abstract
Mechanosensing is essential for several physiological functions including touch and pain sensations, osmoregulation, and controlling the myogenic tone of resistance arteries. Understanding how mechanosensitive ion channels (MSCs) are gated can provide important information regarding these processes. We have previously demonstrated that during pathological conditions such as polycystic kidney disease, polycystin 2 (TRPP2) inhibits the activity of potassium-selective MSCs through a filamin A-mediated cytoskeletal effect, and renders tubular epithelial cells susceptible to apoptosis. However, the nature of this cytoskeletal inhibition remains poorly understood. In this study we use a combination of electrophysiology, structured illumination microscopy, and fluorescence recovery after photobleaching (FRAP) to examine the dynamic nature of the TRPP2-mediated cytoskeletal inhibition of the potassium-selective MSC TREK1. Our data indicate that this inhibition of MSC activity occurs through an accelerated cytoskeletal inhibition, and ultimately decreases the open probability of the TREK1 channel. These results shed light on a novel mode of regulation of MSCs gating, which may be at play in several physiological functions.
Highlights
In the case of the F-actin cytoskeleton, its effect on regulating channel activity can differ based on the geometrical arrangement of its filaments
We use a combination of electrophysiology, imaging with chimeric filamin A (FLNa), structured illumination microscopy (SIM), and fluorescence recovery after photobleaching (FRAP) approaches to examine the nature of the inhibitory effect of FLNa and the F-actin cytoskeleton on TREK1, a potassium-selective mechanosensitive ion channels (MSCs)
We have previously demonstrated that TRPP2 significantly reduces the mechanical activation of TREK1 through a FLNa-dependent mechanism[18]
Summary
In the case of the F-actin cytoskeleton, its effect on regulating channel activity can differ based on the geometrical arrangement of its filaments. It has been proposed that in the presence of the actin crosslinker filamin A (FLNa), fibers are assembled into an orthogonal network[26] that exerts a greater inhibitory effect on the open probability (Po) of MSCs9. This geometry can reduce the membrane radius of curvature and decrease the lateral tension in that domain, effectively reducing channel Po9. This structural rearrangement only reduces the channels’ Po, not their absolute number in the membrane This was demonstrated using the polymodal MSC TREK1, which can be activated by both mechanical stimuli and intracellular acidosis[27]. We use a combination of electrophysiology, imaging with chimeric FLNa, structured illumination microscopy (SIM), and FRAP approaches to examine the nature of the inhibitory effect of FLNa and the F-actin cytoskeleton on TREK1, a potassium-selective MSC
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
