TY - JOUR
T1 - Activity-Dependent Synaptogenesis
T2 - Regulation by a CaM-Kinase Kinase/CaM-Kinase I/βPIX Signaling Complex
AU - Saneyoshi, Takeo
AU - Wayman, Gary
AU - Fortin, Dale
AU - Davare, Monika
AU - Hoshi, Naoto
AU - Nozaki, Naohito
AU - Natsume, Tohru
AU - Soderling, Thomas R.
N1 - Funding Information:
We want to thank Drs. Gary Banker and Stefanie Kaech for advise and consultation throughout this study, Drs. Kohji Fukunaga, Hiroshi Tokumitsu, Michiyuki Matsuda, Ayse Dosemeci, Shelley Halpain, and Gary Bokoch for reagents and Dr. John Scott for use of the imaging facility for the Raichu-Rac experiments. This work was supported by NIH grant NS027037 (T.R.S.). T.S. was supported by the Human Frontier Science Program, D.F. from training grant DK007680, N.H. from NIH grant GM48231 (JD Scott), and T.N. was supported by the New Energy and Industrial Technology Development Organization of Japan.
PY - 2008/1/10
Y1 - 2008/1/10
N2 - Neuronal activity augments maturation of mushroom-shaped spines to form excitatory synapses, thereby strengthening synaptic transmission. We have delineated a Ca2+-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) βPIX and GIT1 that is localized in spines. CaMKI-mediated phosphorylation of Ser516 in βPIX 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 βPIX Ser516Ala mutant, decreases spine formation and mEPSC frequency. Constitutively-active Pak1, a downstream effector of Rac1, rescues spine inhibition by dnCaMKI or βPIX S516A. This activity-dependent signaling pathway can promote synapse formation during neuronal development and in structural plasticity.
AB - Neuronal activity augments maturation of mushroom-shaped spines to form excitatory synapses, thereby strengthening synaptic transmission. We have delineated a Ca2+-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) βPIX and GIT1 that is localized in spines. CaMKI-mediated phosphorylation of Ser516 in βPIX 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 βPIX Ser516Ala mutant, decreases spine formation and mEPSC frequency. Constitutively-active Pak1, a downstream effector of Rac1, rescues spine inhibition by dnCaMKI or βPIX S516A. This activity-dependent signaling pathway can promote synapse formation during neuronal development and in structural plasticity.
KW - CELLBIO
KW - MOLNEURO
KW - SIGNALING
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U2 - 10.1016/j.neuron.2007.11.016
DO - 10.1016/j.neuron.2007.11.016
M3 - Article
C2 - 18184567
AN - SCOPUS:37549027648
SN - 0896-6273
VL - 57
SP - 94
EP - 107
JO - Neuron
JF - Neuron
IS - 1
ER -