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Correlation between Ca(2+) oscillation and cell proliferation via CCK(B)/gastrin receptor
K Akagi1, T Nagao, T Urushidani
1Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Hongo, Bunkyo-Ku, Tokyo, Japan.
Biochimica Et Biophysica Acta
|December 11, 1999
Summary
Gastrin receptor (CCK(B)) stimulates cell proliferation, unlike the m3 muscarinic receptor, due to sustained calcium oscillations. Receptor desensitization and persistent calcium signaling are key to trophic effects.
Area of Science:
- Cell Biology
- Molecular Pharmacology
- Signal Transduction
Background:
- Gastrin, acting via the CCK(B) receptor, promotes cell proliferation.
- The m3 muscarinic receptor, also Gq-protein coupled, lacks trophic effects.
- Understanding differential signaling pathways is crucial for cell growth regulation.
Purpose of the Study:
- To investigate the molecular mechanisms underlying the differential trophic effects of CCK(B) and m3 muscarinic receptors.
- To elucidate the role of calcium signaling and receptor desensitization in cell proliferation.
Main Methods:
- Stable transfection of Chinese Hamster Ovary (CHO) cells with human CCK(B) and m3 receptors.
- Stimulation assays to measure cell growth and MAP kinase activation.
- Intracellular calcium ([Ca(2+)](i)) measurements and analysis of extracellular calcium dependency.
- Receptor truncation and chimeric receptor construction to assess functional domains.
Main Results:
- CCK(B) receptor stimulation, but not m3, increased cell growth.
- Both receptors activated MAP kinase similarly, indicating shared initial signaling.
- CCK(B) induced sustained [Ca(2+)](i) oscillations, while m3 response desensitized.
- Sustained [Ca(2+)](i) oscillations and the CCK(B) receptor's C-terminal region were essential for DNA synthesis.
Conclusions:
- Receptor desensitization plays a critical role in determining cell proliferation.
- Persistent calcium oscillations, mediated by the CCK(B) receptor, are essential for gastrin-induced trophic signaling.
- The C-terminal domain of the CCK(B) receptor is crucial for its proliferative effects.