Abstract
This study examined the effect of dopamine on DNA synthesis and its related signal cascades in mouse embryonic stem (ES) cells. Dopamine inhibited DNA synthesis in both a dose‐ and time‐dependent manner. Dopamine, SKF 38393 (D1 receptor agonist), and quinpirole (D2 receptor agonist) decreased the level of [^3^H]‐thymidine incorporation. The level of cyclic adenosine 3, 5‐monophosphate (cAMP) was increased by SKF 38393 but not by quinpirole. The protein kinase C (PKC) protein was translocated from the cytosolic fraction to the membrane compartment by dopamine. Dopamine also increased [Ca^2+^]~i~, which was blocked by EGTA (an extracellular Ca^2+^ chelator), BAPTA‐AM (an intracellular Ca^2+^ chelator), nifedipine (a L‐type Ca^2+^ channel blocker), SQ 22536 [an adenylyl cyclase (AC) inhibitor] and neomycin [a phospholipase C (PLC) inhibitor]. Dopamine, SKF 38393, and quinpirole increased the level of p44/42 mitogen‐activated protein kinases (MAPKs), p38 MAPK, and stress‐activated protein kinase/Jun‐N‐terminal kinase (SAPK/JNK) phosphorylation. Dopamine also increased level of H~2~O~2~ formation and activated the transcription factor family NF‐κB. Moreover, SKF 38393, quinpirole, and dopamine inhibited cell cycle regulatory proteins, which is consistent with the change in the level of [^3^H]‐thymidine incorporation observed. The dopamine‐induced decrease in cyclin E, cyclin‐dependent protein kinase‐2 (CDK‐2), and cyclin D1, CDK‐4 were blocked by pertussis toxin (G protein inhibitor), SQ 22536, neomycin, bisindolylmaleimide I (PKC inhibitor), SB 203580 (p38 MAPK inhibitor), PD 98059 (p44/42 inhibitor), and SP 600125 (SAPK/JNK inhibitor). In conclusion, dopamine inhibits DNA synthesis in mouse ES cells via the cAMP, Ca^2+^/PKC, MAPKs, and NF‐κB signaling pathways. J. Cell. Physiol. 208: 399–406, 2006. © 2006 Wiley‐Liss, Inc.