Altered cAMP signaling induced by lysophosphatidic acid in senescent human diploid fibroblasts.
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 Gi alpha 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.
Jang
Ik-Soon
IS
Department of Biochemistry, Seoul National University College of Medicine, 28 Yon-gon-Dong, Chongno-Gu, 110-799, Seoul, Republic of Korea
Yeo
Eui-Ju
EJ
Park
Ji-Ae
JA
Ahn
Jeong Soo
JS
Park
Jeong Soo
JS
Cho
Kyung A
KA
Juhnn
Yong-Sung
YS
Park
Sang-Chul
SC
D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism; D000375:Aging / Q000502:physiology*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D015290:Second Messenger Systems / Q000502:physiology*
D008246:Lysophospholipids; D020033:Protein Isoforms; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D000262:Adenylyl Cyclases