Divergent regulation of GAP-43 expression and CNS neurite outgrowth by cyclic AMP.
Robust process outgrowth and high expression of the growth-associated protein GAP-43 seem to be intrinsic features of neurons, but both are down-regulated after axonal contact of target cells. We report that chronic exposure of the serotonergic CNS cell line RN46A to cyclic AMP analogs, forskolin, or cholera toxin represses GAP-43 expression in a dose dependent manner. Thus, cAMP could mediate a GAP-43 repressive signal that is initiated extracellularly. Activation of the cyclic AMP pathway by these same reagents, however, enhances the rate that RN46A cells extend neurites. This stimulation of neurite growth can occur during inhibition of new transcription, and in the absence of high levels of GAP-43. These findings demonstrate that a GAP-43-repressing intracellular signaling pathway exists, that repression of GAP-43 expression by cAMP is not directly coupled to inhibition of neurite growth, and that acceleration of growth cone advancement by cAMP is not dependent on the presence of GAP-43.
Andersen
P L
PL
Cameco MS Neuroscience Research Center and Department of Anatomy and Cell Biology, University of Saskatchewan School of Medicine, Saskatoon, Canada.
Webber
C A
CA
Whittemore
S R
SR
Schreyer
D J
DJ
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology; D003994:Bucladesine / Q000494:pharmacology; D002461:Cell Line, Transformed; D002772:Cholera Toxin / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D019922:GAP-43 Protein / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D016501:Neurites / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000502:physiology / Q000648:ultrastructure; D010641:Phenotype; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011903:Raphe Nuclei / Q000166:cytology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D019922:GAP-43 Protein; D010726:Phosphodiesterase Inhibitors; D010566:Virulence Factors, Bordetella; D005576:Colforsin; D003994:Bucladesine; D002772:Cholera Toxin; D000242:Cyclic AMP; D015056:1-Methyl-3-isobutylxanthine