Aldosterone is a major contributor to the pathophysiology of congestive heart failure. Aldosterone production is Ca2+ dependent and low-voltage activated (LVA) Ca2+ channels are major carriers of Ca current in the aldosterone-producing cells of the adrenal glomerulosa. However, little is known about how hormones control the activity of LVA channels. The recent cloning of three members of the LVA Ca2+ channel family offers the possibility to define the molecular mechanisms involved. The development of drugs that target these channels will provide a new therapeutic strategy to suppress the production of aldosterone in hypertension and congestive heart failure. In the zona glomerulosa, Ca/CaM-dependent protein kinaseII activity increases the frequency of opening of _1H channels at negative voltages, and angiotensin II controls CaMkinase activity. A model system has been developed based on heterologous expression of a CaMKII subunit with _ H1 that mimics the native regulation of the channel. Molecular biology, biochemistry and electrophysiology will be used to test the hypothesis that important components of both long- and short-term regulation of aldosterone secretion elicited by AngII depend on the activity of the _ H1 channels.
The specific aims are to determine which CaMKII isoforms are capable of stimulating LVA channels; to determine which domains on _ 1H channels are important for CaMKII regulation of its activity; and to determine then importance of changes in LVA Ca2+ channel activity on the secretion of aldosterone stimulated by AngII.
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