Dopamine regulates cell cycle regulatory proteins via cAMP, Ca(2+)/PKC, MAPKs, and NF-kappaB in mouse embryonic stem cells

J Cell Physiol. 2006 Aug;208(2):399-406. doi: 10.1002/jcp.20674.

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-kappaB. 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-kappaB signaling pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / pharmacology
  • Adenine / analogs & derivatives
  • Adenine / pharmacology
  • Animals
  • Calcium / metabolism*
  • Calcium Channel Blockers / pharmacology
  • Chelating Agents / pharmacology
  • DNA / biosynthesis
  • DNA / metabolism
  • Dopamine / pharmacology*
  • Dose-Response Relationship, Drug
  • Egtazic Acid / analogs & derivatives
  • Egtazic Acid / pharmacology
  • MAP Kinase Signaling System / drug effects*
  • MAP Kinase Signaling System / physiology
  • Mice
  • NF-kappa B / metabolism*
  • Neomycin / pharmacology
  • Nifedipine / pharmacology
  • Protein Kinase C / metabolism*
  • Quinpirole / pharmacology
  • Receptors, Dopamine D1 / agonists
  • Receptors, Dopamine D2 / agonists
  • Stem Cells / cytology
  • Stem Cells / drug effects*
  • Stem Cells / metabolism
  • Thymidine / metabolism
  • Time Factors

Substances

  • Calcium Channel Blockers
  • Chelating Agents
  • NF-kappa B
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • 1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester
  • 9-(tetrahydro-2-furyl)-adenine
  • Quinpirole
  • Egtazic Acid
  • 2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
  • DNA
  • Protein Kinase C
  • Neomycin
  • Nifedipine
  • Adenine
  • Calcium
  • Thymidine
  • Dopamine