title: 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 hypo-osmotic 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.
authors.affiliation: the Department of Anesthesiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0531, the Department of Pharmacology, Hebei Medical University, Shijiazhuang, Hebei Province 050017, China, and.
authors.forename: Zhanfeng
authors.initials: Z
authors.lastname: Jia
authors.affiliation: the Department of Anesthesiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0531, the Department of Orthopedic Surgery, Jikei University School of Medicine, 3-25-8 Nishi-Shinbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Ikeda
authors.affiliation: the Department of Anesthesiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0531, From the Department of Anesthesiology and Perioperative Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ling
authors.affiliation: From the Department of Anesthesiology and Perioperative Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294.
authors.forename: Viacheslav
authors.initials: V
authors.lastname: Viatchenko-Karpinski
authors.affiliation: the Department of Anesthesiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0531, From the Department of Anesthesiology and Perioperative Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294, gujo@uc.edu.
authors.forename: Jianguo G
authors.initials: JG
authors.lastname: Gu
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D008297:Male; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D009475:Neurons, Afferent / Q000166:cytology / Q000378:metabolism*; D009997:Osmotic Pressure / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013500:Surface Tension
chemical_list: D007473:Ion Channels; C000589132:PIEZO2 protein, human; C000589204:piezo2 protein, rat
keywords: dorsal root ganglia; ion channel; mechanically activated currents; mechanotransduction; membrane tension; neuron; pain; piezo2 channels; plasma membrane