Activity-dependent synaptogenesis: regulation by a CaM-kinase kinase/CaM-kinase I/betaPIX signaling complex.
Neuronal activity augments maturation of mushroom-shaped spines to form excitatory synapses, thereby strengthening synaptic transmission. We have delineated a Ca(2+)-signaling pathway downstream of the NMDA receptor that stimulates calmodulin-dependent kinase kinase (CaMKK) and CaMKI to promote formation of spines and synapses in hippocampal neurons. CaMKK and CaMKI form a multiprotein signaling complex with the guanine nucleotide exchange factor (GEF) betaPIX and GIT1 that is localized in spines. CaMKI-mediated phosphorylation of Ser516 in betaPIX enhances its GEF activity, resulting in activation of Rac1, an established enhancer of spinogenesis. Suppression of CaMKK or CaMKI by pharmacological inhibitors, dominant-negative (dn) constructs and siRNAs, as well as expression of the betaPIX Ser516Ala mutant, decreases spine formation and mEPSC frequency. Constitutively-active Pak1, a downstream effector of Rac1, rescues spine inhibition by dnCaMKI or betaPIX S516A. This activity-dependent signaling pathway can promote synapse formation during neuronal development and in structural plasticity.
Saneyoshi
Takeo
T
Vollum Institute, Oregon Health and Sciences University, Portland, OR 97239, USA.
Wayman
Gary
G
Fortin
Dale
D
Davare
Monika
M
Hoshi
Naoto
N
Nozaki
Naohito
N
Natsume
Tohru
T
Soderling
Thomas R
TR
D000818:Animals; D000831:Animals, Newborn; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism*; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000528:radiation effects; D009154:Mutation / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques / Q000379:methods; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D064067:Rho Guanine Nucleotide Exchange Factors; D012694:Serine / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013569:Synapses / Q000502:physiology*; D014162:Transfection / Q000379:methods
D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D020662:Guanine Nucleotide Exchange Factors; D034741:RNA, Small Interfering; D064067:Rho Guanine Nucleotide Exchange Factors; D012694:Serine; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1