Regulation of Piezo2 Mechanotransduction by Static Plasma Membrane Tension in Primary Afferent Neurons

Abstract Piezo2 channel is a newly identified mammalian mechanical transducer that confers rapidly adapting mechanically activated (RA-MA) currents in primary afferent neurons. Piezo2 channels sense rapid membrane displacement but it is not clear if they are sensitive to osmotic swelling which slowly increases static plasma membrane tension (SPMT). Here we show that SPMT exerts profound impact on the mechanical sensitivity of RA-MA channels in primary afferent neurons. RAMA currents are greatly enhanced and mechanical threshold reduced in both primary afferent neurons of rat dorsal root ganglia (DRG) and HEK293 cells heterologously expressing Piezo2 when these cells undergo osmotic swelling to increase SPMT. Osmotic swelling switches the kinetics of RA-MA currents to slowly adapting type in both cultured DRG neurons and HEK293 cells heterologously expressing Piezo2. The potentiation of RAMA currents is abolished when cultured DRG neurons are treated with cytochalasin D (CD), an actin filament disruptor that prevents SPMT of cultured DRG neurons from increase by osmotic swelling. Osmotic swelling significantly increases DRG neuron mechano-excitability such that a subthreshold mechanical stimulus can result in action potential firing. Behaviorally, mechanical hindpaw withdrawal threshold in rats is reduced following the injection of a hypotonic solution, but this osmotic effect is JBC abolished when CD or Gd3+ is coadministered with the hypo-osmotic solution. Taken together, our findings suggest that Piezo2-mediated mechanotransduction is regulated by SPMT in primary afferent neurons. Since STMP can be changed by multiple biological factors, our findings may have broad implications in mechanical sensitivity under physiological and pathological conditions.