Project: Research project

Project Details


Aldosterone secretion from the adrenal glomerulosa cell is
regulated by a number of secretagogues. Most of these agents
probably mediate their effects, at least in part, via the calcium
messenger system. In the case of AII, it is thought that upon
hormone binding there is an activation of a membrane
phosphodiesterase which breaks down phosphatidylinositol 4,5
bisphosphate to inositol 1,4,5 trisphosphate and diacylglycerol.
The former causes intracellular calcium release, thus activating a
calmodulin-dependent protein kinase, while the latter is thought to
activate membrane bound, protein kinase C. Key events take
place at three levels: 1) hormone-receptor interaction; 2)
membrane-associated events, and 3) intracellular events. The
goal of this study is to more fully characterize the events
occurring at each of these levels and integrate them into a
comprehensive model of hormone action. The studies on hormone-
receptor interaction will first focus on whether there is a guanine
nucleotide binding protein linking the receptor to the
phosphodiesterase and, if so, we will attempt to isolate and
characterize this protein. Next, the cellular substrates and
temporal patterns of phsophatidylinositol turnover will be
determined with radioactive labeling and chromatographic
techniques. What role these products may have as second
messengers will also be evaluated. The studies on membrane-
associated events will focus on determining if there is a Na+/H+
exchanger in glomerulosa cells and if there is, what role it plays
in signal transduction. The role of the membrane associated C-
kinase will be evaluated by using immunocytochemical
localization techniques. The studies on intracellular events will
focus on what role protein kinase (CaM/PK II, C-kinase, M-kinase)
may play in signal propagation. Using 32P or 35S labeling, the
existence of a "labile" protein will be documented, and a
determination will be made as to whether or not it is the link
between the changes in protein kinase activity and actual
synthesis and secretion of aldosterone. The importance of these
studies is two-fold. First, aldosterone is involved in salt and
water homeostasis and thus plays a role in multiple pathological
states. By understanding the mechanisms of regulation of
aldosterone secretion, we may be able to favorably alter their
course. Second, the hormone-receptor interactions being studied
take place not only in the adrenal glomerulosa cell but in a
variety of cells throughout the body. Thus, principles derived
from these studies may also apply to the hormonal regulation of
cellular responses in these other tissues.
StatusNot started


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