Piezo1 and Piezo2 Are Essential Components of Distinct Mechanically Activated Cation Channels

Mechanical Responders Identified Although many cells appear to respond to mechanical stimulation through increased conductance of ion channels in the plasma membrane, the actual channels that mediate these effects—which are important in diverse processes from hearing and touch to control of blood pressure—have remained elusive. Coste et al. (p. 55, published online 2 September) used RNA interference to decrease expression of candidate genes systematically in a mouse neuroblastoma cell line and identified two genes that encode proteins, Piezo1 and Piezo2, which are required for mechanically stimulated cation conductance in these cells and in cultured dorsal root ganglion neurons. Similar proteins are expressed in a range of species from protozoa to vertebrates. The proteins are not similar to known pore-forming proteins and thus could be unusual channels or regulatory components of a channel complex. Cation channel genes encode for a transducer molecule that converts mechanical stimuli into cell signaling. Mechanical stimuli drive many physiological processes, including touch and pain sensation, hearing, and blood pressure regulation. Mechanically activated (MA) cation channel activities have been recorded in many cells, but the responsible molecules have not been identified. We characterized a rapidly adapting MA current in a mouse neuroblastoma cell line. Expression profiling and RNA interference knockdown of candidate genes identified Piezo1 (Fam38A) to be required for MA currents in these cells. Piezo1 and related Piezo2 (Fam38B) are vertebrate multipass transmembrane proteins with homologs in invertebrates, plants, and protozoa. Overexpression of mouse Piezo1 or Piezo2 induced two kinetically distinct MA currents. Piezos are expressed in several tissues, and knockdown of Piezo2 in dorsal root ganglia neurons specifically reduced rapidly adapting MA currents. We propose that Piezos are components of MA cation channels.

[1]  C. Haslett,et al.  Integrin activation by Fam38A uses a novel mechanism of R-Ras targeting to the endoplasmic reticulum , 2010, Journal of Cell Science.

[2]  Manuela Schmidt,et al.  Nociceptive Signals Induce Trafficking of TRPA1 to the Plasma Membrane , 2009, Neuron.

[3]  F. Sachs,et al.  Polycystin-1 and -2 Dosage Regulates Pressure Sensing , 2009, Cell.

[4]  David Julius,et al.  Cellular and Molecular Mechanisms of Pain , 2009, Cell.

[5]  S. Gilroy,et al.  Feeling green: mechanosensing in plants. , 2009, Trends in cell biology.

[6]  P. Delmas,et al.  Ciliar functions in the nephron , 2009, Pflügers Archiv - European Journal of Physiology.

[7]  G. Burnstock Purinergic mechanosensory transduction and visceral pain , 2009, Molecular pain.

[8]  Jonathan E. Gale,et al.  High-Threshold Mechanosensitive Ion Channels Blocked by a Novel Conopeptide Mediate Pressure-Evoked Pain , 2007, PloS one.

[9]  Rabih Moshourab,et al.  A stomatin-domain protein essential for touch sensation in the mouse , 2007, Nature.

[10]  Patrick Delmas,et al.  Pharmacological Dissection and Distribution of NaN/Nav1.9, T-type Ca2+ Currents, and Mechanically Activated Cation Currents in Different Populations of DRG Neurons , 2007, The Journal of general physiology.

[11]  Gary R Lewin,et al.  Mechanosensitive currents in the neurites of cultured mouse sensory neurones , 2006, The Journal of physiology.

[12]  Y. Gwack,et al.  Orai1 is an essential pore subunit of the CRAC channel , 2006, Nature.

[13]  K. Kosaka,et al.  A novel membrane protein, encoded by the gene covering KIAA0233, is transcriptionally induced in senile plaque-associated astrocytes , 2006, Brain Research.

[14]  U. Oh,et al.  A novel mechanosensitive channel identified in sensory neurons , 2006, The European journal of neuroscience.

[15]  S. Earley,et al.  Critical Role for Transient Receptor Potential Channel TRPM4 in Myogenic Constriction of Cerebral Arteries , 2004, Circulation research.

[16]  Gary R Lewin,et al.  Mechanosensation and pain. , 2004, Journal of neurobiology.

[17]  D. Cockayne,et al.  Acid‐sensing ion channels ASIC2 and ASIC3 do not contribute to mechanically activated currents in mammalian sensory neurones , 2004, The Journal of physiology.

[18]  A. Patapoutian,et al.  Noxious Cold Ion Channel TRPA1 Is Activated by Pungent Compounds and Bradykinin , 2004, Neuron.

[19]  D. McKemy,et al.  Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1 , 2004, Nature.

[20]  Richard O Hynes,et al.  Integrins Bidirectional, Allosteric Signaling Machines , 2002, Cell.

[21]  Frederick Sachs,et al.  High-speed pressure clamp , 2002, Pflügers Archiv.

[22]  John N. Wood,et al.  Distinct Mechanosensitive Properties of Capsaicin-Sensitive and -Insensitive Sensory Neurons , 2002, The Journal of Neuroscience.

[23]  S. Lawson Phenotype and Function of Somatic Primary Afferent Nociceptive Neurones with C‐, Aδ‐ or Aα/β‐Fibres , 2002, Experimental physiology.

[24]  Bonnie A. Wallace,et al.  Structure and function of voltage-dependent ion channel regulatory β subunits , 2002 .

[25]  K. R. Spring,et al.  Bending the MDCK Cell Primary Cilium Increases Intracellular Calcium , 2001, The Journal of Membrane Biology.

[26]  B. Hille,et al.  Ionic channels of excitable membranes , 2001 .

[27]  O. Hamill,et al.  Molecular basis of mechanotransduction in living cells. , 2001, Physiological reviews.

[28]  J. Levine,et al.  Mechanical transduction by rat dorsal root ganglion neurons in vitro , 1999, Neuroscience Letters.

[29]  F. Ashcroft,et al.  A touching case of channel regulation: the ATP-sensitive K+ channel , 1998, Current Opinion in Neurobiology.

[30]  H. Sann,et al.  RT97: a marker for capsaicin-insensitive sensory endings in the rat skin , 1995, Cell and Tissue Research.

[31]  K. Iwatsuki,et al.  Induction of the thigmotaxis in Paramecium caudatum. , 1995, Comparative biochemistry and physiology. Part A, Physiology.

[32]  H. Gainer,et al.  NF‐L and peripherin immunoreactivities define distinct classes of rat sensory ganglion cells , 1991, Journal of neuroscience research.

[33]  J. Garson,et al.  A monoclonal antibody against neurofilament protein specifically labels a subpopulation of rat sensory neurones , 1984, The Journal of comparative neurology.

[34]  A. Hudspeth,et al.  Response latency of vertebrate hair cells. , 1979, Biophysical journal.

[35]  I. Kiseleva,et al.  Mechanosensitivity of the Nervous System , 2009 .

[36]  J. Ruppersberg Ion Channels in Excitable Membranes , 1996 .