Saturday, December 21, 2024
12/21/2024
ABSTRACT: The sense of touch is critical for daily tasks including tactile discrimination, social interaction, and environmental exploration. The overall objective of this project is to identify the cellular and molecular mechanisms underlying the sense of touch in mammals. Previous studies have shown that Merkel discs, a main type of tactile end organ, play a central role in the sense of touch. Merkel discs are located in touch sensitive spots throughout the body especially at human fingertips and whisker hair follicles of non-primate mammals. A Merkel disc consists of a Merkel cell and an Aβ-afferent ending (Merkel ending) to form a synapse-like structure. We and others have previous shown that the Piezo2 channel on Merkel cells is the sensor of touch. We have further shown that tactile stimuli activate Piezo2 channels in Merkel cells to result in Ca2+-action potentials, which leads to Aβ-afferent impulses and behavioral tactile responses. However, the mechanism by which tactile-induced excitatory signals on Merkel cells are transmitted to Merkel endings remains elusive and is the focus of this renewal application. Our central hypothesis is that acid sensing ion channels (ASICs) are the excitatory postsynaptic receptors and proton is the principal transmitter to mediate excitatory postsynaptic currents (EPSCs) and synaptic transmission at Merkel discs. We will test this novel hypothesis with the following specific aims. Aim 1. Characterize the fundamental nature of EPSCs at Merkel endings of Aβ-afferent fibers. Aim 2. Demonstrate that EPSCs are mediated by ASICs located at Merkel endings. Aim 3. Elucidate that activation of ASICs by protons is responsible for the generation of EPSCs at Merkel endings. Aim 4. Identify the isoform of functional ASICs that mediate EPSCs at Merkel endings. Pressure-patch-clamp recordings will be applied at the heminode of Merkel endings in rodent whisker hair follicles to record EPSCs that are evoked by mechanical stimulation, and other techniques including synaptic physiology, pharmacology, immunohistochemistry, and mouse genetics will be used to achieve the above aims. By completing the above aims, we will have uncovered a new fundamental mechanism mediating synaptic transmission of tactile signals at Merkel discs. This will significantly advance scientific knowledge about molecular mechanisms underlying the sense of touch. It may also have important implications in mechanical sensory dysfunctions (e.g., loss of touch sensation) seen under clinical conditions such as diabetes and chemotherapy.
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