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The Journal of Neuroscience, May 14, 2008, 28(20):5369-5382; doi:10.1523/JNEUROSCI.4738-07.2008

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Cellular/Molecular
Phosphorylation of Homer3 by Calcium/Calmodulin-Dependent Kinase II Regulates a Coupling State of Its Target Molecules in Purkinje Cells

Akihiro Mizutani,^1,3 Yukiko Kuroda,¹ Akira Futatsugi,^1,4 Teiichi Furuichi,² and Katsuhiko Mikoshiba^1,4

¹Laboratory for Developmental Neurobiology and ²Laboratory for Molecular Neurogenesis, Brain Science Institute, The Institute of Physical and Chemical Research (RIKEN), Wako, Saitama 351-0198, Japan, ³Department of Basic Medical Sciences, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan, and ⁴Calcium Oscillation Project, ICORP-SORST, Japan Science and Technology Agency, Wako, Saitama 351-0198, Japan

Correspondence should be addressed to Katsuhiko Mikoshiba, Laboratory for Developmental Neurobiology, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Email: mikosiba{at}brain.riken.jp

Homer proteins are components of postsynaptic density (PSD) and play a crucial role in coupling diverse target molecules. However, the regulatory aspect of Homer-mediated coupling has been addressed only about a dominant-negative effect of Homer1a, which requires de novo gene expression. Here, we present evidence that Homer-mediated coupling is regulated by its phosphorylation state. We found that Homer3, the predominant isoform in Purkinje cells, is phosphorylated by calcium/calmodulin-dependent protein kinase II (CaMKII) both in vitro and in vivo. Biochemical fractionation with phosphor-specific antibodies revealed the presence of phosphorylated Homer3 in the cytosolic fraction in contrast to high levels of nonphosphorylated Homer3 in PSD. In P/Q-type voltage-gated-Ca²⁺ channel knock-out mice, in which CaMKII activation was reduced, the levels of Homer3 phosphorylation and the soluble form of Homer 3 were markedly lower. Furthermore, both robust phosphorylation of Homer3 and its dissociation from metabotropic glutamate receptor 1 (mGluR1) were triggered by depolarization in primary cultured Purkinje cells, and these events were inhibited by CaMKII inhibitor. An in vitro binding kinetic analysis revealed that these phosphorylation-dependent events were attributable to a decrease in the affinity of phosphorylated Homer3 for its ligand. In a heterologous system, the Ca²⁺ signaling pattern induced by mGluR1 activation was modulated by the Homer3 phosphorylation state. Together, these findings suggested that Homer3 in Purkinje cells might function as a reversible coupler regulated by CaMKII phosphorylation and that the phosphorylation is capable of regulating the postsynaptic molecular architecture in response to synaptic activity.

Key words: Purkinje cells; Homer; phosphorylation; CaMKII; synaptic plasticity; Ca²⁺ signaling

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Received Oct. 19, 2007; revised Feb. 19, 2008; accepted March 21, 2008.

Correspondence should be addressed to Katsuhiko Mikoshiba, Laboratory for Developmental Neurobiology, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan. Email: mikosiba{at}brain.riken.jp

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