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

Min Young Lee1, Jung Sun Heo, Ho Jae Han

  • 1Department of Veterinary Physiology, College of Veterinary Medicine, Chonnam National University, Gwangju, Korea.

Journal of Cellular Physiology
|May 12, 2006
PubMed

Insights

Dopamine significantly inhibits DNA synthesis in mouse embryonic stem cells. This effect is mediated through complex signaling pathways including cyclic adenosine monophosphate, calcium/protein kinase C, mitogen-activated protein kinases, and nuclear factor-kappaB.

Area of Science:

  • Molecular Biology
  • Stem Cell Biology
  • Neuroscience

Background:

  • Dopamine's role in cellular processes beyond neurotransmission is an area of ongoing research.
  • Embryonic stem cells (ESCs) possess unique properties of self-renewal and differentiation, making them crucial for developmental studies.
  • Understanding the molecular mechanisms regulating DNA synthesis in ESCs is fundamental for regenerative medicine and developmental biology.

Purpose of the Study:

  • To investigate the impact of dopamine on DNA synthesis in mouse embryonic stem cells.
  • To elucidate the specific intracellular signaling cascades involved in dopamine's effect on DNA synthesis.
  • To identify the key molecular players and pathways mediating dopamine's influence on ESC proliferation.

Main Methods:

  • Assessed DNA synthesis using [(3)H]-thymidine incorporation in mouse ESCs.
  • Utilized receptor agonists (SKF 38393 for D1, quinpirole for D2) and antagonists to probe dopamine receptor involvement.
  • Measured intracellular signaling molecules including cyclic adenosine 3, 5-monophosphate (cAMP), intracellular calcium ([Ca(2+)](i)), protein kinase C (PKC) translocation, mitogen-activated protein kinases (MAPKs) phosphorylation, and reactive oxygen species (H(2)O(2)).
  • Analyzed the expression of cell cycle regulatory proteins (cyclin E, CDK-2, cyclin D1, CDK-4) and activated transcription factors (NF-kappaB).
  • Employed pharmacological inhibitors for various signaling pathways (adenylyl cyclase, phospholipase C, PKC, MAPKs) and G protein signaling (pertussis toxin).

Main Results:

  • Dopamine significantly inhibited DNA synthesis in mouse ESCs in a dose- and time-dependent manner.
  • Dopamine, D1 and D2 receptor agonists reduced [(3)H]-thymidine incorporation, indicating receptor-mediated effects.
  • Dopamine modulated intracellular signaling, including increased cAMP (via D1), PKC translocation, elevated [Ca(2+)](i), enhanced MAPK phosphorylation (p44/42, p38, JNK), increased H(2)O(2) formation, and NF-kappaB activation.
  • Dopamine treatment led to decreased levels of key cell cycle proteins (cyclin E, CDK-2, cyclin D1, CDK-4).
  • Inhibitors of cAMP, Ca(2+)/PKC, MAPKs, NF-kappaB, and G protein signaling blocked the dopamine-induced inhibition of cell cycle proteins and DNA synthesis.

Conclusions:

  • Dopamine exerts an inhibitory effect on DNA synthesis in mouse embryonic stem cells.
  • This inhibition is mediated through multiple signaling pathways: cyclic adenosine monophosphate (cAMP), calcium/protein kinase C (Ca(2+)/PKC), mitogen-activated protein kinases (MAPKs), and nuclear factor-kappaB (NF-kappaB).
  • The findings reveal a novel role for dopamine in regulating ESC proliferation via intricate molecular signaling networks.

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