Multiple Desensitization Mechanisms of Mechanotransducer Channels Shape Firing of Mechanosensory Neurons

How desensitization of mechanotransducer currents regulates afferent signal generation in mammalian sensory neurons is essentially unknown. Here, we dissected desensitization mechanisms of mechanotransducer channels in rat sensory neurons that mediate the sense of touch and pain. We identified four types of mechanotransducer currents that distribute differentially in cutaneous nociceptors and mechanoreceptors and that differ in desensitization rates. Desensitization of mechanotransducer channels in mechanoreceptors was fast and mediated by channel inactivation and adaptation, which reduces the mechanical force sensed by the transduction channel. Both processes were promoted by negative voltage. These properties of mechanotransducer channels suited them to encode the dynamic parameters of the stimulus. In contrast, inactivation and adaptation of mechanotransducer channels in nociceptors had slow time courses and were suited to encode duration of the stimulus. Thus, desensitization properties of mechanotransducer currents relate to their functions as sensors of phasic and tonic stimuli and enable sensory neurons to achieve efficient stimulus representation.

[1]  J. Gybels,et al.  Nociceptor discharges and sensations due to prolonged noxious mechanical stimulation — A paradox Hum. Neurobiol., 3 (1984) 53–58 , 1985, Pain.

[2]  D P Corey,et al.  Two mechanisms for transducer adaptation in vertebrate hair cells. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Patrick Delmas,et al.  Inflammatory Mediators Increase Nav1.9 Current and Excitability in Nociceptors through a Coincident Detection Mechanism , 2008, The Journal of general physiology.

[4]  Boris Martinac,et al.  Mechanosensitive ion channels: molecules of mechanotransduction , 2004, Journal of Cell Science.

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

[6]  R. Fettiplace,et al.  The sensory and motor roles of auditory hair cells , 2006, Nature Reviews Neuroscience.

[7]  A J Ricci,et al.  The Endogenous Calcium Buffer and the Time Course of Transducer Adaptation in Auditory Hair Cells , 1998, The Journal of Neuroscience.

[8]  J. Levine,et al.  Ionic basis of a mechanotransduction current in adult rat dorsal root ganglion neurons , 2006, Molecular pain.

[9]  M G Evans,et al.  The actions of calcium on the mechano‐electrical transducer current of turtle hair cells. , 1991, The Journal of physiology.

[10]  N. Hacohen,et al.  Regulation of tension on hair-cell transduction channels: displacement and calcium dependence , 1989, The Journal of neuroscience : the official journal of the Society for Neuroscience.

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

[12]  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.

[13]  O. Hamill,et al.  Rapid adaptation of single mechanosensitive channels in Xenopus oocytes. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[14]  D P Corey,et al.  Voltage dependence of adaptation and active bundle movement in bullfrog saccular hair cells. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[15]  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.

[16]  D P Corey,et al.  Adaptation of mechanoelectrical transduction in hair cells of the bullfrog's sacculus , 1987, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[17]  Makoto Tsunozaki,et al.  Mammalian somatosensory mechanotransduction , 2009, Current Opinion in Neurobiology.

[18]  O. Hamill,et al.  Twenty odd years of stretch-sensitive channels , 2006, Pflügers Archiv.

[19]  M G Evans,et al.  Activation and adaptation of transducer currents in turtle hair cells. , 1989, The Journal of physiology.

[20]  J. Wood,et al.  The mechanosensitive cell line ND-C does not express functional thermoTRP channels , 2009, Neuropharmacology.

[21]  A. Hudspeth,et al.  Identification of a 120 kd hair-bundle myosin located near stereociliary tips , 1993, Neuron.

[22]  L. Drew,et al.  Kinetic properties of mechanically activated currents in spinal sensory neurons , 2010, The Journal of physiology.

[23]  Gary R Lewin,et al.  Evidence for a protein tether involved in somatic touch , 2010, The EMBO journal.

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

[25]  A J Hudspeth,et al.  Detection of Ca2+ entry through mechanosensitive channels localizes the site of mechanoelectrical transduction in hair cells. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[26]  U. Müller,et al.  Mechanotransduction by Hair Cells: Models, Molecules, and Mechanisms , 2009, Cell.

[27]  H. Handwerker,et al.  Discharge patterns of afferent cutaneous nerve fibers from the rat's tail during prolonged noxious mechanical stimulation , 2004, Experimental Brain Research.

[28]  X. L. Zhou,et al.  A mechanosensitive ion channel in the yeast plasma membrane. , 1988, Science.

[29]  F. Sachs,et al.  Bilayer-dependent inhibition of mechanosensitive channels by neuroactive peptide enantiomers , 2004, Nature.

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

[31]  Sergei Sukharev,et al.  The “Dashpot” Mechanism of Stretch-dependent Gating in MscS , 2005, The Journal of general physiology.

[32]  Ellen A. Lumpkin,et al.  Mechanisms of sensory transduction in the skin , 2007, Nature.

[33]  Leonard K. Kaczmarek,et al.  Protein Kinase Modulation of a Neuronal Cation Channel Requires Protein–Protein Interactions Mediated by an Src homology 3 Domain , 2002, The Journal of Neuroscience.

[34]  Ling Xie,et al.  Alzheimer's β-Amyloid Peptides Compete for Insulin Binding to the Insulin Receptor , 2002, The Journal of Neuroscience.

[35]  D. Corey,et al.  The micromachinery of mechanotransduction in hair cells. , 2007, Annual review of neuroscience.

[36]  Patrick Delmas,et al.  Gating and modulation of presumptive NaV1.9 channels in enteric and spinal sensory neurons , 2004, Molecular and Cellular Neuroscience.

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

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