Arginase I and polyamines act downstream from cyclic AMP in overcoming inhibition of axonal growth MAG and myelin in vitro.
Elevation of cAMP can overcome myelin inhibitors to encourage regeneration of the CNS. We show that a consequence of elevated cAMP is the synthesis of polyamines, resulting from an up-regulation of Arginase I, a key enzyme in their synthesis. Inhibiting polyamine synthesis blocks the cAMP effect on regeneration. Either over-expression of Arginase I or exogenous polyamines can overcome inhibition by MAG and by myelin in general. While MAG/myelin support the growth of young DRG neurons, they become inhibitory as DRGs mature. Endogenous Arginase I levels are high in young DRGs but drop spontaneously at an age that coincides with the switch from promotion to inhibition by MAG/myelin. Over-expressing Arginase I in maturing DRGs blocks that switch. Arginase I and polyamines are more specific targets than cAMP for intervention to encourage regeneration after CNS injury.
Cai
Dongming
D
Biology Department, Hunter College, City University of New York, 695 Park Avenue, New York, NY 10024, USA.
Deng
Kangwen
K
Mellado
Wilfredo
W
Lee
Junghee
J
Ratan
Rajiv R
RR
Filbin
Marie T
MT
D000818:Animals; D001119:Arginase / Q000096:biosynthesis* / Q000235:genetics; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D003994:Bucladesine / Q000494:pharmacology; D016466:CHO Cells; D002490:Central Nervous System / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism*; D018076:DNA, Complementary / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D020439:Growth Cones / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008969:Molecular Sequence Data; D009186:Myelin Sheath / Q000378:metabolism*; D018992:Myelin-Associated Glycoprotein / Q000096:biosynthesis*; D009414:Nerve Growth Factors / Q000494:pharmacology; D009416:Nerve Regeneration / Q000502:physiology; D011073:Polyamines / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011700:Putrescine / Q000494:pharmacology; D051381:Rats; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D019208:Brain-Derived Neurotrophic Factor; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D018992:Myelin-Associated Glycoprotein; D009414:Nerve Growth Factors; D011073:Polyamines; D003994:Bucladesine; D000242:Cyclic AMP; D001119:Arginase; D011700:Putrescine