Expression of PKC substrate proteins, GAP-43 and neurogranin, is downregulated by cAMP signaling and alterations in synaptic activity.
Growth-associated protein 43 (GAP-43) and neurogranin are protein kinase C substrate proteins that are thought to play an important role in synaptic plasticity, but little is currently known about the mechanisms that may regulate their function at the synapse. In this study, we show that long-term elevation of intracellular cAMP levels in rat primary cortical cultures results in a persistent downregulation of GAP-43 and neurogranin, most likely at the transcriptional level. This effect may be at least partially mediated by protein kinase A, but is independent of protein kinase C activation. Moreover, it is mimicked and occluded by manipulations that alter the levels of spontaneous synaptic activity in primary cultures, such as bicuculline and tetrodotoxin. These data suggest that levels of GAP-43 and neurogranin are regulated by factors known to modulate synaptic strength, thus providing a potential mechanism by which protein kinase C signaling pathways and their substrates might contribute to synaptic function and/or plasticity.
Krueger
Dilja D
DD
Department of Psychiatry, Division of Molecular Psychiatry, Yale University School of Medicine, Ribicoff Research Facilities, CMHC, 34 Park Street, New Haven, CT 06508, USA.
Nairn
Angus C
AC
D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D002540:Cerebral Cortex / Q000166:cytology; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D004347:Drug Interactions; D004622:Embryo, Mammalian; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D019922:GAP-43 Protein / Q000235:genetics / Q000378:metabolism*; D051579:Neurogranin / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors
D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D018756:GABA Antagonists; D019922:GAP-43 Protein; D012333:RNA, Messenger; D026941:Sodium Channel Blockers; D051579:Neurogranin; D005576:Colforsin; D013779:Tetrodotoxin; D000242:Cyclic AMP; D001640:Bicuculline