Molecular characterization of slowly inactivating mechanically activated ion channels in dorsal root ganglion neurons

Scripps Research Institute, The, La Jolla CA

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Abstract

? DESCRIPTION (provided by applicant): Our sense of touch provides critical information about our physical environment by transforming innocuous and noxious mechanical energy into electrical signals. Sensing and transducing physical forces such as pressure and stretch are important aspects of somatosensory and nociceptive signaling. Decades ago it was postulated that ion channels in specialized mechanosensitive sensory cells open in response to pressure. Mechanosensitive neurons respond to particular aspects of a stimulus (e.g., movement vs. sustained pressure) and display different adaptation properties in vivo and in vitro. The identification of Piezo proteins as mechanically activated (MA) ion channels has provided insights into the nature of sensors of touch (somatosensation), fluid shear force (endothelial cells) and stretch (gut or organ distension). When expressed in a variety mammalian cell lines, Piezo proteins confer large rapidly inactivating MA non-selective cationic currents during indentation of somata with a blunt glass probe. Remarkably, Piezo2 was recently identified as the major ion channel used for sensing touch and fiber recordings provided strong evidence that touch and pain sensations are separable. Therefore, yet-unknown mechanically activated ion channel(s) must account for noxious (painful) mechanosensation (Ranade, Woo, Dubin et al., in press) and they mediate the slowly inactivating currents observed in about half the small diameter DRG neurons. We propose to take an innovative approach using Next Generation Sequencing (RNA-Seq) to identify genes encoding the elusive slowing inactivating MA channel(s) in DRG neurons. RELEVANCE: Vibration, gentle touch, and painful mechanical stimuli are distinct modes of force detected by a heterogeneous population of mammalian mechanosensory neurons. Although much effort has focused on identifying slowly inactivating ion channels in sensory neurons that transduce noxious (painful) mechanical stimuli, they remain elusive. We propose to take an innovative approach using Next Generation sequencing to identify genes encoding ion channels mediating slowing inactivating mechanically activated currents in DRG neurons.