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https://hdl.handle.net/2142/21873
Description
Title
Cellular mechanisms of angiotensin release
Author(s)
Gadbut, Albert Peter
Issue Date
1991
Doctoral Committee Chair(s)
Weyhenmeyer, James A.
Department of Study
Biology
Discipline
Biology
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Biology, Neuroscience
Biology, Cell
Language
eng
Abstract
In this study we examined angiotensin (ANG) release from primary cultured rat brain cells in response to ion stimulation and ligands that stimulate or inhibit second messenger systems in an attempt to understand how the release of ANG is regulated.
Results indicated that ANG release could be stimulated in a dose dependent fashion by increasing concentrations of K+. This suggests that ANG secretion resembles a neurotransmitter-like release as opposed to a volume transmission-like secretion. Angiotensin release was inhibited by voltage gated calcium channel (VGCC) antagonists Cd$\sp{++}$ and $\omega$-Conotoxin GIVA ($\omega$-CgTx), but only slightly by nitrendipine. This suggests that extracellular Ca$\sp{++}$ is involved in ANG release. Furthermore, the N-type VGCC seems to be the primary VGCC type responsible for Ca$\sp{++}$ entrance into the cell leading to ANG release.
To examine the potential effect of the Ca$\sp{++}$ binding protein calmodulin on ANG release the cells in culture were K$\sp+$ stimulated in the presence of the calmodulin antagonists W-7 and W-13. The calmodulin antagonists W-7 and W-13 both blocked ANG release in a dose dependent fashion with W-13 being a more potent blocker of ANG release. These data suggest extracellular Ca$\sp{++}$ enters the cell and activates calmodulin to facilitate ANG release.
We found that ANG release could be stimulated by isoproterenol, the cholera toxin, forskolin, and 8-bromo-c-AMP. This suggests a receptor linked mechanism, whereby the $\beta$-adrenergic receptor is linked via G-protein to the activation of adenylate cyclase and c-AMP, regulating the release of angiotensin from brain cells in culture.
The Ca$\sp{++}$/calmodulin system and the adenylate cyclase/c-AMP system reportedly (Kennedy, 1989) co-modulate each other in several systems. To examine this potential interaction, cultured cells were stimulated with isoproterenol or forskolin in the presence of W-7, W-13 or Cd$\sp{++}$. The release of ANG was attenuated in response to isoproterenol/W-13, isoproterenol/Cd$\sp{++}$ and forskolin/W-7 as compared to isoproterenol or forskolin alone. However, the level of attenuation was different from that observed by W-13, W-7 or Cd$\sp{++}$ alone. This suggests that Ca$\sp{++}$/calmodulin and adenylate cyclase systems are both capable of stimulating ANG release independently and that some modulatory interaction does exist between the two systems.
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