Opposite effects of two PKA inhibitors on cAMP inhibition of IGF-I-induced oligodendrocyte development: a problem of unspecificity?
The stimulatory effect of insulin-like growth factor I (IGF-I) on myelin basic protein (MBP) expression, a parameter for oligodendrocyte development, is mediated by the MAPK and PI3K signaling pathways. We have previously shown that the second messenger cAMP inhibits IGF-I-induced MAPK activation as well as MBP expression. We also showed that the PKA inhibitor Rp-cAMPS reverted the cAMP effect on IGF-I-induced MBP without affecting the cAMP effect on IGF-I-induced MAPK activation. Here we report that, in contrast to Rp-cAMPS, H89 (a PKA inhibitor structurally non-related to Rp-cAMPS) enhances both the inhibitory effect of cAMP on IGF-I-induced MBP expression and the inhibitory effect of cAMP on IGF-I-induced MAPK activation. Likewise, H89 is capable of inhibiting the IGF-I-induced MAPK activation in the absence of PKA stimulation. Thus, we hypothesize that an unspecific action of H89 on a target located upstream MAPK could account for the discrepancies between the effects elicited by Rp-cAMPS and H89.
Palacios
Nuria
N
Endocrinology Department, Hospital Ramón y Cajal, Carretera de Colmenar, Km 9, 28034 Madrid, Spain.
Sánchez-Franco
Franco
F
Fernández
Miriam
M
Sánchez
Isabel
I
Villuendas
Gemma
G
Cacicedo
Lucinda
L
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003470:Culture Media; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D004789:Enzyme Activation / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D004676:Myelin Basic Protein / Q000096:biosynthesis; D009836:Oligodendroglia / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity; D013449:Sulfonamides / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology
D003470:Culture Media; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D004676:Myelin Basic Protein; D013449:Sulfonamides; D013873:Thionucleotides; C016957:adenosine-3',5'-cyclic phosphorothioate; D007334:Insulin-Like Growth Factor I; D000242:Cyclic AMP; D019869:Phosphatidylinositol 3-Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide