Determining the influence of neuronal mechanics on touch-evoked mechanoreceptor currents

PROJECT SUMMARY Whether due to injury, disease, or as a consequence of cancer chemotherapy, millions of Americans, both young and old, experience sensory neuropathy. This condition, characterized by numbness, tingling, and disruptions to gait, degrades the quality of life. The sheer diversity of cells that underpin the mechanical senses of touch, hearing, and proprioception pose a barrier to understanding their function in health and their dysfunction in disease. Rapid mechanosensation responsible for low-threshold touch sensation depends on the activation of specialized mechanosensitive (MS) ion channels. The proteins forming MS channels in humans and other animals have come to light over the past two decades, yet how mechanical energy causes their activation remains poorly understood. Some MS channels seem to respond to changes in membrane tension, others depend on coupling to the cytoskeleton, and still others require coupling to extracellular matrix (ECM) structures. Whereas a subset of neuropathies arise from faulty nerve transmission, many other forms involve defects in coupling MS channels to sensory stimulation or from defects in the channels themselves. This project seeks to understand how sensory stimuli is coupled to MS channel activation in vivo. Very few biological models are amenable to in vivo neuronal biophysics, including voltage-clamp of sensory neurons and to imaging MS channel complexes in living animals. The model organism C. elegans fulfills these requirements. In this research we will combine established techniques for in vivo whole-cell patch-clamp electrophysiology with cutting-edge, genetically encoded tools to visualize and measure touch-induced mechanical strain in touch receptor neurons. A large toolbox of existing mutations affecting the cytoskeleton and ECM will be used to perturb the coupling between sensory stimulation and MS channel activation, delineating the role played by each structure in this fundamental sensory process. Ample evidence indicates that the mechanics of touch are conserved even among distantly related animals, suggesting that what is learned through this research training plan has the potential to provide insight into the factors that give rise to sensory neuropathy and to other mechanosensory abnormalities.