Purinergic stimulation of cell division and differentiation: mechanisms and pharmacological implications.
Extracellular purine nucleosides and nucleotides in micromolar concentrations stimulate proliferation of a variety of cell types in vitro and in vivo. As well they act synergistically with NGF to stimulate neurite outgrowth from PC12 cells. A variety of purine nucleosides and deoxyribonucleosides promote cell proliferation and increase intracellular cAMP. Their activities are inhibited by adenosine A2 receptor antagonists. Only adenosine interacts with the A2 receptor. We propose that the other nucleosides and deoxyribonucleosides inhibit extracellular adenosine deaminase, thereby increasing the extracellular concentration of adenosine. The nucleotides apparently act by stimulating P2y receptors coupled to inositol phosphate metabolism. We propose that the nucleosides and nucleotides act synergistically with other growth factors because each has distinct but complementary second messenger systems. If our hypotheses are correct, it should prove possible to modulate the growth and morphogenesis in several cell types using drugs that inhibit or stimulate adenosine A2 or purine P2y receptor agonists or the second messenger systems coupled to these receptors.
Rathbone
M P
MP
Department of Biomedical Sciences, McMaster University Health Science Centre, Hamilton, Ontario, Canada.
Deforge
S
S
Deluca
B
B
Gabel
B
B
Laurenssen
C
C
Middlemiss
P
P
Parkinson
S
S
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology*; D006133:Growth Substances / Q000494:pharmacology; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D008954:Models, Biological; D011684:Purine Nucleosides / Q000494:pharmacology; D011685:Purine Nucleotides / Q000494:pharmacology; D011983:Receptors, Purinergic / Q000145:classification / Q000187:drug effects / Q000502:physiology*
D006133:Growth Substances; D007295:Inositol Phosphates; D011684:Purine Nucleosides; D011685:Purine Nucleotides; D011983:Receptors, Purinergic