Determinants of Mechanotransduction Sensitivity

Stanford University, Stanford CA

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Abstract

? DESCRIPTION (provided by applicant): The sense of touch is vital for interacting with the world around us. Increases in sensitivity to touch, as in hyperalgesia or allodynia, and loss of sensation, as in diabetic or chemotherapy-induced peripheral neuropathy, can both diminish quality of life. Some of these changes in somatosensation may occur at the molecular level in the primary sensory neurons, yet how the first responders in touch detect a mechanical stimulus is still a mystery. We know neither how the initial ion channel opening occurs in mechanotransduction, nor how differences in the transfer of mechanical energy to and through the channel can affect the sensitivity of the neuron to touch. The overall goal of this proposal is to investigate how sensitivity to mechanical stimuli is affected by the structure of mechanotransduction channels and by the environment that surrounds them. Genetic and morphological variation among somatosensory neurons allows us to sense inputs ranging from a puff of air to a painful scrape. In C. elegans, different classes of mechanoreceptor neurons transduce mechanical stimuli with differing levels of sensitivity, making it a useful model system for studying mechanosensitivity. Working with this genetically tractable model allows us to investigate the properties of these channels within their natural environment. Previous work in our lab provides evidence that different channels expressed in distinct neurons exhibit different sensitivity to force. In preliminary studies, I found differences in constitutive currents between heterologously expressed wild-type MEC-4 channels and chimeric channels containing segments of the homologous DEG-1 channel. In the proposed research, I will use these chimeric channels to explore the role of various channel domains in determining the sensitivity of a given neuron within a specific environment. Other work from our lab has shown that the composition of the plasma membrane affects the ability of worms to sense touch. I will investigate the specific effects of these membrane manipulations on mechanotransduction. By increasing our understanding of the molecular mechanisms that underlie differences in mechanosensitivity, we may be better able to predict the molecular and cellular changes occurring in sensitization disorders and peripheral neuropathy.