Displacement of α-Actinin from the NMDA Receptor NR1 C0 Domain By Ca2+/Calmodulin Promotes CaMKII Binding

Michelle A Merrill; Zulfiqar Malik; Zeynep Akyol; Jason A Bartos; A Soren Leonard; Andy Hudmon; Madeline A Shea; Johannes W Hell

doi:10.1021/bi0623025

Back

Displacement of α-Actinin from the NMDA Receptor NR1 C0 Domain By Ca2+/Calmodulin Promotes CaMKII Binding

Journal article

Open access

Peer reviewed

Displacement of α-Actinin from the NMDA Receptor NR1 C0 Domain By Ca2+/Calmodulin Promotes CaMKII Binding

Michelle A Merrill, Zulfiqar Malik, Zeynep Akyol, Jason A Bartos, A Soren Leonard, Andy Hudmon, Madeline A Shea and Johannes W Hell

Biochemistry (Easton), Vol.46(29), pp.8485-8497

07/24/2007

DOI: 10.1021/bi0623025

PMCID: PMC2547089

PMID: 17602661

Files and links (1)

url

http://doi.org/10.1021/bi0623025View

Open Access

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.

Signal Transduction

Protein Structure, Tertiary

Calmodulin - metabolism

Calcium - metabolism

Humans

Receptors, N-Methyl-D-Aspartate - metabolism

Rats

Recombinant Fusion Proteins - metabolism

Animals

Receptors, N-Methyl-D-Aspartate - chemistry

Recombinant Fusion Proteins - genetics

Binding Sites

Calcium-Calmodulin-Dependent Protein Kinase Type 2

Calcium-Calmodulin-Dependent Protein Kinases - metabolism

Actinin - metabolism

Details

Title: Subtitle: Displacement of α-Actinin from the NMDA Receptor NR1 C0 Domain By Ca2+/Calmodulin Promotes CaMKII Binding
Creators: Michelle A Merrill - Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242-1109, USA
Zulfiqar Malik
Zeynep Akyol
Jason A Bartos
A Soren Leonard
Andy Hudmon
Madeline A Shea
Johannes W Hell
Resource Type: Journal article
Publication Details: Biochemistry (Easton), Vol.46(29), pp.8485-8497
DOI: 10.1021/bi0623025
PMID: 17602661
PMCID: PMC2547089
NLM abbreviation: Biochemistry
ISSN: 0006-2960
eISSN: 1520-4995
Publisher: United States
Grant note: GM057001 / NIGMS NIH HHS R01 NS046450-01 / NINDS NIH HHS R01 NS046450-02 / NINDS NIH HHS R01 NS046450-04 / NINDS NIH HHS R01 GM057001-05A2 / NIGMS NIH HHS R01 NS046450-03 / NINDS NIH HHS R01 GM057001 / NIGMS NIH HHS R01 NS046450 / NINDS NIH HHS NS046450 / NINDS NIH HHS R01 GM057001-06 / NIGMS NIH HHS This work was supported by NIH Grants NS046450 (to J.W.H.) and GM057001 (to M.A.S.).
Language: English
Date published: 07/24/2007
Academic Unit: Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Biochemistry and Molecular Biology
Record Identifier: 9984024527402771

Metrics

11 Record Views

38 Times Cited - Web of Science