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

Abstract

The Piezo2 channel is a newly identified mammalian mechanical transducer that confers rapidly adapting mechanically activated (RA-MA) currents in primary afferent neurons. The Piezo2 channels sense rapid membrane displacement, but it is not clear whether they are sensitive to osmotic swelling, which slowly increases static plasma membrane tension (SPMT). Here, we show that SPMT exerts a profound impact on the mechanical sensitivity of RA-MA channels in primary afferent neurons. RA-MA currents are greatly enhanced, and the mechanical threshold was 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 the slowly adapting type in both cultured DRG neurons and HEK293 cells heterologously expressing Piezo2. The potentiation of RA-MA currents is abolished when cultured DRG neurons are treated with cytochalasin D, an actin filament disruptor that prevents SPMT of cultured DRG neurons from an 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, the mechanical hind paw withdrawal threshold in rats is reduced following the injection of a hypotonic solution, but this osmotic effect is abolished when cytochalasin D or Gd 3؉ is co-administered with the hypoosmotic solution. Taken together, our findings suggest that Piezo2-mediated mechanotransduction is regulated by SPMT in primary afferent neurons. Because SPMT can be changed by multiple biological factors, our findings may have broad implications in mechanical sensitivity under physiological and pathological conditions.

Molecular basis of tactile specialization in the duck bill

“…The rate of Piezo2 inactivation controls the amount of excitatory charge entering the cell upon mechanical stimulation. Inactivation of Piezo2 and its homolog Piezo1 can be prolonged at positive potentials (34,48), by mutations (49)(50)(51)(52)(53)(54)(55), pharmacologically (56,57), or by the destruction of the cytoskeleton or after repeated stimulation (58), fluid shear stress (59), or osmotic swelling (60). These data establish that Piezo channel kinetics is modulated by intracellular factors.…”

Mechanical sensitivity and electrophysiological properties of acutely dissociated dorsal root ganglion neurons of rats

“…IA and SA currents in Noci-MS DRG neurons may be mediated by tentonin 3, another recently identified MA channels that display slower kinetics (10), or unidentified MA channels. Some IA and SA currents could also be due to the alteration of Piezo2 channel inactivation kinetics due to osmotic swelling (16). …”

Touch, Tension, and Transduction – The Function and Regulation of Piezo Ion Channels

“…First, although a cytoskeletal network is not required for mechanosensitivity of Piezo1, its bi-directional influence on tension sensitivity has been demonstrated in inside-out patches, cytoskeleton-deficient blebbed membranes, and by pharmacological disruption and osmotic swelling [44, 45, 67, 68]. Second, Piezo1 and Piezo2 are sensitized by the integral membrane protein STOML3, which recruits cholesterol to the membrane, thus likely increasing membrane stiffness and facilitating force transfer to the channel [47, 69].…”