The gentlest breeze, the roughest sandpaper, and the sharpest pin are detected by our somatosensory system, which is composed of thousands of touch-sensitive mechanoreceptor neurons embedded in the skin. It is widely understood that physical force is transduced into neural signals through activation of specialized ion channels (called 'mechano-electrical transduction'or MeT channels), but understanding of the molecular and physical basis of this process remains rudimentary. All animals have the ability to sense touch and recent work has shown that nematode and mammalian somatosensory neurons have similar response dynamics (reviewed in Geffeney and Goodman, Neuron 74:609, 2012). This functional conservation is seen in neurons that rely on either DEG/ENaC or TRP channel proteins to form MeT channels, a finding which implies that response properties are conferred primarily by the cellular environment and not intrinsic to the ion channel proteins. The long-term goal of the proposed research program is to understand how the cell membrane and cytoskeleton regulate the delivery of physical force to MeT channels expressed in touch receptor neurons (TRNs) and discover the structural rearrangements associated with touch-evoked MeT channel gating. The general approach will be to combine in vivo recording of MeT channel gating in identified TRNs with genetic perturbations in C. elegans nematodes that 1) alter biosynthesis of polyunsaturated fatty acids and cell membrane function, 2) disrupt the microtubule and spectrin cytoskeleton and 3) disrupt selected domains in the MEC-4 proteins crucial to the formation of the sodium-selective native MeT channels,. This work will be paired with optogenetics studies designed to identify factors that affect MeT channels, but not downstream signaling events and with biophysical analysis of MeT channels expressed in heterologous cells. The proposed research combines expertise in sensory biophysics, in vivo electrical recording from identified C. elegans neurons, genetic analysis, to derive a profound understanding of the sense of touch. What is learned from these studies has the potential to improve understanding of touch sensation and its dysfunction in disease, during chemotherapy and as a consequence of normal aging.

Public Health Relevance

Our sense of the touch is the earliest to develop, last to fade and the least understood. In a syndrome called peripheral neuropathy, touch sensitivity declines with age and is severely impaired in diabetes, by HIV and by chemotherapy. There is no treatment for sensory neuropathy beyond palliative care. The proposed research exploits simple animal models to develop a comprehensive understanding of how touch acts on ion channel mechanosensors, cell membranes, and cell skeletons to give rise to touch sensation and our work has the potential to lead to treatments that may prevent or alleviate sensory neuropathy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS047715-09A1
Application #
8629261
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Gnadt, James W
Project Start
2003-12-01
Project End
2018-05-31
Budget Start
2013-09-01
Budget End
2014-05-31
Support Year
9
Fiscal Year
2013
Total Cost
$394,291
Indirect Cost
$138,887
Name
Stanford University
Department
Biophysics
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Krieg, Michael; Dunn, Alexander R; Goodman, Miriam B (2014) Mechanical control of the sense of touch by ?-spectrin. Nat Cell Biol 16:224-33
Richardson, Claire E; Spilker, Kerri A; Cueva, Juan G et al. (2014) PTRN-1, a microtubule minus end-binding CAMSAP homolog, promotes microtubule function in Caenorhabditis elegans neurons. Elife 3:e01498
Vásquez, Valeria; Krieg, Michael; Lockhead, Dean et al. (2014) Phospholipids that contain polyunsaturated fatty acids enhance neuronal cell mechanics and touch sensation. Cell Rep 6:70-80
Chalfie, Martin; Hart, Anne C; Rankin, Catharine H et al. (2014) Assaying mechanosensation. WormBook :
Frederic, Melissa Y; Lundin, Victor F; Whiteside, Matthew D et al. (2013) Identification of 526 conserved metazoan genetic innovations exposes a new role for cofactor E-like in neuronal microtubule homeostasis. PLoS Genet 9:e1003804
Petzold, Bryan C; Park, Sung-Jin; Mazzochette, Eileen A et al. (2013) MEMS-based force-clamp analysis of the role of body stiffness in C. elegans touch sensation. Integr Biol (Camb) 5:853-64
Glauser, Dominique A; Johnson, Brandon E; Aldrich, Richard W et al. (2011) Intragenic alternative splicing coordination is essential for Caenorhabditis elegans slo-1 gene function. Proc Natl Acad Sci U S A 108:20790-5
Geffeney, Shana L; Cueva, Juan G; Glauser, Dominique A et al. (2011) DEG/ENaC but not TRP channels are the major mechanoelectrical transduction channels in a C. elegans nociceptor. Neuron 71:845-57
Petzold, Bryan C; Park, Sung-Jin; Ponce, Pierre et al. (2011) Caenorhabditis elegans body mechanics are regulated by body wall muscle tone. Biophys J 100:1977-85
Johnson, Brandon E; Glauser, Dominique A; Dan-Glauser, Elise S et al. (2011) Alternatively spliced domains interact to regulate BK potassium channel gating. Proc Natl Acad Sci U S A 108:20784-9

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