Ion Channels in Mechanosensitive Neurons

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DESCRIPTION (provided by applicant): The long-term objective of this project is to understand the generation and transmission of mechanosensory information from the baroreceptor sensory terminal to its central termination in the nucleus of the solitary tract. This is part of a broader research effort to determine the neurophysiological and neuroanatomical substrate that underlies neural regulation of arterial pressure and cardiac rhythm. In this grant we are examining the distribution and the function of a new family of ion channels, the TRPC family of calcium permeable cation channels. These channels are important because they serve as a source of calcium influx that is expected to modulate the pattern of neuronal activity through effects on membrane potential, transmitter release at the central terminals and sensory discharge at the peripheral terminals. There are four specific aims: the first examines the distribution of the TRPC channels in the baroreceptor afferent fibers. Using immunohistochemistry, we will define the location of TRPC channels in the baroreceptor afferent pathway in three regions: the peripheral sensory receptors of myelinated and unmyelinated fibers in the arch of the aorta, in their soma in the nodose ganglion and in their synaptic terminals in the nucleus of the solitary tract. In the second aim we will ask what ligands activate these channels using an electrophysiological characterization of the channels in cell-attached patches and whole cell current in perforated patch whole cell recording. In the third aim we pursue the mechanism of activation by examining the effect of agonist on calcium influx using calcium imaging techniques to evaluate the contribution of the TRPC channels relative to the voltage-gated channels. Finally, in aim four we explore the functional consequence of activation of specific TRPC channels in whole cell voltage recording. These studies will include RNA interference to eliminate specific channels.