Activity-Dependent Synaptogenesis: Regulation by a CaM-Kinase Kinase/CaM-Kinase I/βPIX Signaling Complex

Takeo Saneyoshi; Gary Wayman; Dale Fortin; Monika Davare; Naoto Hoshi; Naohito Nozaki; Tohru Natsume; Thomas R. Soderling

doi:10.1016/j.neuron.2007.11.016

Activity-Dependent Synaptogenesis: Regulation by a CaM-Kinase Kinase/CaM-Kinase I/βPIX Signaling Complex

Takeo Saneyoshi
, Gary Wayman
, Dale Fortin
, Monika Davare
, Naoto Hoshi
, Naohito Nozaki
, Tohru Natsume
, Thomas R. Soderling

Pediatric Hematology and Oncology

Research output: Contribution to journal › Article › peer-review

197 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	94-107
Number of pages	14
Journal	Neuron
Volume	57
Issue number	1
DOIs	https://doi.org/10.1016/j.neuron.2007.11.016
State	Published - Jan 10 2008

Funding

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.

Funders	Funder number
Author National Institutes of Health National Institutes of Health National Institutes of Health National Institutes of Health The Bev Hartig Huntington's Disease Foundation National Institutes of Health	NS027037
National Institute of General Medical Sciences	R37GM048231
Human Frontier Science Program	DK007680
New Energy and Industrial Technology Development Organization

Keywords

CELLBIO
MOLNEURO
SIGNALING

ASJC Scopus subject areas

General Neuroscience

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10.1016/j.neuron.2007.11.016

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title = "Activity-Dependent Synaptogenesis: Regulation by a CaM-Kinase Kinase/CaM-Kinase I/βPIX Signaling Complex",

abstract = "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.",

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author = "Takeo Saneyoshi and Gary Wayman and Dale Fortin and Monika Davare and Naoto Hoshi and Naohito Nozaki and Tohru Natsume and Soderling, \{Thomas R.\}",

note = "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. ",

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AU - Davare, Monika

AU - Hoshi, Naoto

AU - Nozaki, Naohito

AU - Natsume, Tohru

AU - Soderling, Thomas R.

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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.

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Activity-Dependent Synaptogenesis: Regulation by a CaM-Kinase Kinase/CaM-Kinase I/βPIX Signaling Complex

Abstract

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Keywords

ASJC Scopus subject areas

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