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

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Ca2+ influx through the N-methyl-D-aspartate (NMDA)-type glutamate receptor triggers activation and postsynaptic accumulation of Ca 2+/calmodulin-dependent kinase II (CaMKII). CaMKII, calmodulin, and α-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 α-actinin from NR1 C0 upon Ca2+ influx. We show that Ca2+-depleted calmodulin and α-actinin simultaneously bind to NR1 C0. Upon addition of Ca2+, calmodulin dislodges α-actinin. Either the N- or C-terminal half of calmodulin is sufficient for Ca2+-induced displacement of α-actinin. Whereas α-actinin directly antagonizes CaMKII binding to NR1 C0, the addition of Ca2+/calmodulin shifts binding of NR1 C0 toward CaMKII by displacing α-actinin. Displacement of α-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.

Original languageEnglish
Pages (from-to)8485-8497
Number of pages13
JournalBiochemistry
Volume46
Issue number29
DOIs
StatePublished - Jul 24 2007

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Actinin
Calcium-Calmodulin-Dependent Protein Kinases
Calmodulin
N-Methyl-D-Aspartate Receptors
Phosphotransferases
Neuronal Plasticity
Glutamate Receptors
N-Methylaspartate
Membranes
Plasticity

ASJC Scopus subject areas

  • Biochemistry

Cite this

Merrill, M. A., Malik, Z., Akyol, Z., Bartos, J. A., Leonard, A. S., Hudmon, A., ... Hell, J. W. (2007). Displacement of α-actinin from the NMDA receptor NR1 C0 domain by Ca2+/calmodulin promotes CaMKII binding. Biochemistry, 46(29), 8485-8497. https://doi.org/10.1021/bi0623025

Displacement of α-actinin from the NMDA receptor NR1 C0 domain by Ca2+/calmodulin promotes CaMKII binding. / Merrill, Michelle A.; Malik, Zulfiqar; Akyol, Zeynep; Bartos, Jason A.; Leonard, A. Soren; Hudmon, Andy; Shea, Madeline A.; Hell, Johannes W.

In: Biochemistry, Vol. 46, No. 29, 24.07.2007, p. 8485-8497.

Research output: Contribution to journalArticle

Merrill, MA, Malik, Z, Akyol, Z, Bartos, JA, Leonard, AS, Hudmon, A, Shea, MA & Hell, JW 2007, 'Displacement of α-actinin from the NMDA receptor NR1 C0 domain by Ca2+/calmodulin promotes CaMKII binding', Biochemistry, vol. 46, no. 29, pp. 8485-8497. https://doi.org/10.1021/bi0623025
Merrill, Michelle A. ; Malik, Zulfiqar ; Akyol, Zeynep ; Bartos, Jason A. ; Leonard, A. Soren ; Hudmon, Andy ; Shea, Madeline A. ; Hell, Johannes W. / Displacement of α-actinin from the NMDA receptor NR1 C0 domain by Ca2+/calmodulin promotes CaMKII binding. In: Biochemistry. 2007 ; Vol. 46, No. 29. pp. 8485-8497.
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