Displacement of Alpha-actinin from the Nmda Receptor Nr1 C0 Domain By Ca2+/Calmodulin Promotes Camkii Binding.
From: Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242-1109, USA.
Biochemistry
- Publish Date: Jul 2007
- ISSN: 0006-2960
- Volume: 46
- Issue: 29
- Pages: 8485-97
- Medium: Print
- Language: English
- Citation (JAMA): Merrill Michelle A, Malik Zulfiqar, Akyol Zeynep, et al. Displacement of Alpha-actinin from the Nmda Receptor Nr1 C0 Domain By Ca2+/Calmodulin Promotes Camkii Binding.. Biochemistry Jul 2007;46:8485-97
Abstract
Ca2+ influx through the N-methyl-d-aspartate (NMDA)-type glutamate receptor triggers activation and postsynaptic accumulation of Ca2+/calmodulin-dependent kinase II (CaMKII). CaMKII, calmodulin, and alpha-actinin directly bind to the short membrane proximal C0 domain of the C-terminal region of the NMDA receptor NR1 subunit. In a negative feedback loop, calmodulin mediates Ca2+-dependent inactivation of the NMDA receptor by displacing alpha-actinin from NR1 C0 upon Ca2+ influx. We show that Ca2+-depleted calmodulin and alpha-actinin simultaneously bind to NR1 C0. Upon addition of Ca2+, calmodulin dislodges alpha-actinin. Either the N- or C-terminal half of calmodulin is sufficient for Ca2+-induced displacement of alpha-actinin. Whereas alpha-actinin directly antagonizes CaMKII binding to NR1 C0, the addition of Ca2+/calmodulin shifts binding of NR1 C0 toward CaMKII by displacing alpha-actinin. Displacement of alpha-actinin results in the simultaneous binding of calmodulin and CaMKII to NR1 C0. Our results reveal an intricate mechanism whereby Ca2+ functions to govern the complex interactions between the two most prevalent signaling molecules in synaptic plasticity, the NMDA receptor and CaMKII.
Mesh Headings (Keywords): Actinin, Animals, Binding Sites, Calcium, Calcium-Calmodulin-Dependent Protein Kinase Type 2, Calcium-Calmodulin-Dependent Protein Kinases, Calmodulin, Humans, Protein Structure, Tertiary, Rats, Receptors, N-Methyl-D-Aspartate, Recombinant Fusion Proteins, Signal Transduction
Check for Full Text / PubMed Unique Identifier (PMID): 17602661
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