Cdk5-Mediated Phosphorylation of δ-Catenin Regulates Its Localization and GluR2-Mediated Synaptic Activity
- Charlene P. Poore1,*,
- Jeyapriya R. Sundaram1,*,
- Tej K. Pareek3,
- Amy Fu4,
- Niranjana Amin5,
- Nur Ezan Mohamed2,
- Ya-Li Zheng5,
- Angeline X. H. Goh1,
- Mitchell K. Lai2,6,
- Nancy Y. Ip4,
- Harish C. Pant5, and
- Sashi Kesavapany1
- 1Department of Biochemistry, Neurobiology Program, Yong Loo Lin School of Medicine and
- 2Department of Pharmacology, National University of Singapore, Singapore 117597,
- 3Department of Pediatrics, Case Western Reserve University, Cleveland, Ohio 44106,
- 4Department of Biotechnology, Hong Kong University of Science and Technology, Kowloon, Hong Kong 999077, China,
- 5Cytoskeletal Protein Regulation Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, and
- 6Dementia Research Laboratory, Department of Clinical Research, Singapore General Hospital, Singapore 169608
- Correspondence should be addressed to Sashi Kesavapany, Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, MD7, #02-03, Singapore 117597. sashikesavapany{at}gmail.com
-
↵*C.P.P. and J.R.S. contributed equally to this work.
Abstract
Cyclin-dependent kinase 5 (Cdk5)-mediated phosphorylation plays an important role in proper synaptic function and transmission. Loss of Cdk5 activity results in abnormal development of the nervous system accompanied by massive disruptions in cortical migration and lamination, therefore impacting synaptic activity. The Cdk5 activator p35 associates with δ-catenin, the synaptic adherens junction protein that serves as part of the anchorage complex of AMPA receptor at the postsynaptic membrane. However, the implications of Cdk5-mediated phosphorylation of δ-catenin have not been fully elucidated. Here we show that Cdk5-mediated phosphorylation of δ-catenin regulates its subcellular localization accompanied by changes in dendritic morphogenesis and synaptic activity. We identified two Cdk5 phosphorylation sites in mouse δ-catenin, serines 300 and 357, and report that loss of Cdk5 phosphorylation of δ-catenin increased its localization to the membrane. Furthermore, mutations of the serines 300 and 357 to alanines to mimic nonphosphorylated δ-catenin resulted in increased dendritic protrusions accompanied by increased AMPA receptor subunit GluR2 localization at the membrane. Consistent with these observations, loss of Cdk5 phosphorylation of δ-catenin increased the AMPA/NMDA ratio. This study reveals how Cdk5 phosphorylation of the synaptic mediator protein δ-catenin can alter its localization at the synapse to impact neuronal synaptic activity.
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