Mechanism of Mechanoreceptor Inhibition by Aldosterone

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DESCRIPTION (provided by applicant): The long term objective of my lab is to understand the molecular basis of mechanotransduction. This includes the 1) identification of components of mechanosensitive ion channel complexes in sensory neurons and muscle cells, 2) regulation of mechanosensitive channel expression by physical and hormonal factors and 3) involvement in cardiovascular pathophysiology (autonomic dysfunction, hypertension). The current proposal will address a highly novel area of research: aldosterone regulation of mechanosensitive ion channel expression and function. Hypertension and chronic heart failure are characterized by elevations in circulating aldosterone. Aldosterone is known to inhibit baroreceptor function, which may contribute to cardiac arrhythmias frequently associated with these diseases. The molecular mechanism of aldosterone suppression of baroreflex control of the autonomic nervous system is unclear. The hypothesis underlying this proposal is that aldosterone activation of the MAPK signaling pathway, decreases the expression of mechanosensitive channels in baroreceptor neurons by inhibiting transcription and augmenting degradation of ENaC proteins, thus causing baroreceptor dysfunction. This is a novel hypothesis. The goals of this proposal are to determine if 1) aldosterone inhibits DEG/ENaC transcript expression and mechanically gated calcium transients, 2) activation of the MAPK signaling cascade inhibits ENaC expression and mechanically gated calcium transients, and 3) ENaC proteins are required for mechanosensory function in cultured sensory neurons. We will use real time RT-PCR and immunofluorescence to determine the role of aldosterone and MAPK pathway on ENaC expression in cultured sensory neurons. We will use 2 assays to assess mechanosensory function in cultured sensory neurons. The importance of ENaC proteins in mechanotransduction will be determined using interference RNA and overexpression of dominant-negative isoforms. The results from this proposal may help define the molecular mechanism of baroreceptor inhibition by aldosterone and provide a better understanding of the mechanism of autonomic dysfunction in hypertension and chronic heart failure.