The sense of light touch is critically important for daily life but this important sense can be altered to result in sensory dysfunctions such as tactile anesthesia and mechanical allodynia under pathological conditions. How mammals can sense light touch has been one of the biggest mysteries in science. This lack of knowledge prevents development of potentially effective approaches for preventing or treating mechanical sensory dysfunctions. Our long-term-goal is to uncover the cellular and molecular mechanisms underlying the sense of light touch in mammals. As the first stage of our long-term goal, the overall objective of this application is to study mechanisms underlying mechanical transduction of Merkel cell-neurite complex, a sensory structure essential for sensing light touch in mammals. Our central hypothesis is that Merkel cells are mechanical transducer cells that express mechanically activated ion channels (MA) and that activation of these channels triggers Merkel cells to fire action potentials and release excitatory transmitters. This hypothesis is based on ou preliminary results obtained by using our recently developed patch-clamp recordings from Merkel cells situated in whisker hair follicles (Merkel cell in situ patch-clamp technique). This innovative technique has, for the first time, led us to successfully record MA currents from Merkel cells. We have further discovered that Merkel cells in situ fire action potentials in response to mechanical stimulation. Our unique expertise of Merkel cell in situ patch-clamp recording technique places us at an advanced position to test the hypothesis with the following specific aims: 1) Elucidate ionic mechanisms of MA currents that excite Merkel cells in situ and characterize Merkel cell MA channel properties; 2) Identity ion channels that encode mechanical activity in Merkel cells; and 3) Delineate the mechanisms underlying the transmission of mechanical activity by Merkel cells. The outcomes of the above investigations will provide scientific knowledge about the sense of light touch at a cellular and molecular level. The study may have clinical implications ranging from sensory dysfunctions seen in diabetes and other disease conditions to Merkel cell malfunctions such as Merkel cell carcinoma.
The sense of light touch enables tactile discrimination of shapes; texture; vibration and spatial details; and is indispensable in daily life; yet scientific knowledge about how mammals can sense light touch remains lacking at a cellular and molecular level. The expected outcomes of the proposed research will uncover cellular and ion channel mechanisms underlying mechanical transduction for light touch. Because light touch dysfunctions such as the loss of touch sensitivity and the pain induced by light touch are common clinical problems seen under pathological conditions such as diabetes; chemotherapies and other diseases; understanding cellular and molecular mechanisms of light touch may help us better understand the physiopathology of these sensory dysfunctions; and may further lead to new strategies for preventing or treating the sensory dysfunctions.
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