Long-term stimuli of many systems leads to decreased cellular
responsiveness, or desensitization. We characterized the desensitization of
angiotensin II (Ang 11)-mediated inositol phospholipid (IP) hydrolysis in cultured
human aortic smooth muscle cells (HASMC). Although it has been suggested that
the desensitization induced by long-term Mg II exposure may result partially from
down-regulation of Ang II receptor, this is not sufficient to explain fully
desensitization in many systems. Post-receptor desensitization of IP hydrolysis
may also result from phosphorylation or changes in protein levels of the effector
enzyme, PLC-β. We identified the major PLC-β isoenzymes expressed by
HASMC as PLC-β1 and PLC-β3. Ang II pretreatment reduced IP accumulation
induced by Ang II (1μM) in a time-dependent manner. Phorbol ester-12-myristrate-13-acetate (PMA), a protein kinase C (PKC) activator, also reduced
Ang II-stimulated IP accumulation. These results suggest that PKC activation may
negatively regulate Ang II-stimulated IP signaling in HASMC, similar to rat cells.
In addition, PKC also reduced IP accumulation stimulated by A1F₄⁻, directly
activating the G protein. It suggests that the majority of PKC-induced
desensitization of Ang II-stimulated IP signaling occurs downstream of the Ang II
receptor in HASMC. However, both PLC-β1 and PLC-β3, expected candidates for
PKC phosphorylation, were phosphorylated independently of PKC activation or
inhibition, indicating that PKC might not be involved in direct phosphorylation of
PLC-β1 and PLC-β3. Furthermore, PLC-β1, but not PLC-β3, was highly
phosphorylated under basal conditions, suggesting that PLC-β1 and PLC-β3 may
play different roles in IP signaling in HASMC. / Graduation date: 2003
| Identifer | oai:union.ndltd.org:ORGSU/oai:ir.library.oregonstate.edu:1957/30353 |
| Date | 06 March 2003 |
| Creators | Niibori, Yoshiko |
| Contributors | Filtz, Theresa M. |
| Source Sets | Oregon State University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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