Margaric Acid Decreases Sensory Neurons Mechanical Excitability by Inhibiting PIEZO2 Channels

Abstract

The ability to sense mechanical stimuli requires the transduction of an applied force into electrical signals. Mechanosensitive ion channels rely on membrane composition to transduce such stimuli. PIEZO2 is a mechanosensitive ion channel that has been shown to mediate proprioception, light touch, vibration detection, and mechanical pain. Fatty acids can be incorporated into the plasma membrane and dynamically regulate its mechanics and ion channel function. Previous work in our laboratory has shown that supplementation of margaric acid (MA, C17:0) to cultured cells inhibits PIEZO1 activation by increasing the rigidity and bending stiffness of the plasma membrane. Here, we demonstrate that PIEZO2 function is inhibited by MA using fatty acid supplementation and electrophysiology. We found that MA inhibits the activation currents of heterologously expressed Mus musculus PIEZO2 splice variants in a dose dependent manner, without changing their inactivation. Likewise, MA inhibits endogenous mechano-activated currents (rapidly, intermediately, and slowly adapting) in Mus musculus dorsal root ganglia (DRG) cultured neurons and in differentiated Rattus norvegicus (r) DRG neurons. Current-clamp experiments show that MA enrichment inhibits the mechanical excitability of rDRG neurons by increasing the mechanical threshold for action potential firing, without affecting voltage-dependent currents. Finally, we determine that MA inhibits bacterial and plant mechanosensitive ion channels (MscS, MscL, and Osca1.2) by increasing their mechanical threshold for activation. Our current findings demonstrate that the mechanical properties of the plasma membrane modulate the cell's response to mechanical cues and that this might represent a common principle for mechanosensitive ion channels of different kingdoms.