Altered cAMP signaling induced by lysophosphatidic acid in senescent human diploid fibroblasts

• Published in: Biochemical and biophysical research communications Vol. 302; no. 4; pp. 778 - 784
• Main Authors: Jang, Ik-Soon, Yeo, Eui-Ju, Park, Ji-Ae, Soo Ahn, Jeong, Park, Jeong-Soo, A Cho, Kyung, Juhnn, Yong-Sung, Park, Sang Chul
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.03.2003
• Subjects: Adenylyl cyclase; Adenylyl Cyclases - genetics; Adenylyl Cyclases - metabolism; Aging - physiology; cAMP; Cells, Cultured; Cyclic AMP - metabolism; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; Humans; Lysophosphatidic acid; Lysophosphatidic acid receptors; Lysophospholipids - pharmacology; Phosphoric Diester Hydrolases - genetics; Phosphoric Diester Hydrolases - metabolism; Protein Isoforms - genetics; Protein Isoforms - metabolism; Receptors, Cell Surface - genetics; Receptors, Cell Surface - metabolism; Receptors, G-Protein-Coupled; Receptors, Lysophosphatidic Acid; Second Messenger Systems - physiology; Senescence; Lysophosphatidic acid receptors; Senescence; Lysophosphatidic acid; Adenylyl cyclase; cAMP
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/S0006-291X(03)00262-6

Lysophosphatidic acid (LPA) is a lipid mitogen that acts through G-protein-coupled receptors. LPA responsiveness has been reported to be dependent on the senescent state of the cells. To solve the mechanism underlying, we observed LPA-dependent cAMP status and found its age-dependent contrasting profile such as high level of cAMP in the senescent cells vs its low level in the young cells. In order to clarify the molecular mechanism of the ageing effect, we examined various molecular species involved in the cAMP signaling pathway by semi-quantitative RT-PCR. EDG-1 and EDG-4 were unchanged, but EDG-2 and EDG-7 were reduced with age. Senescent cells showed a partial reduction of Gi1, Gi2, and Gi3, but no change in the level of Gq. Decreased Gis and Gi-coupled LPA receptors may reduce the inhibitory effect of Giα on adenylyl cyclases (ACs), resulting in cAMP accumulation via activation of adenylyl cyclase in senescent fibroblasts. We also observed an age-dependent increase in some of AC isoforms: II, IV, and VI. In conclusion, multiple changes in the cAMP signaling pathway of the senescent cells might explain the altered responsiveness to the mitogenic stimuli.