PMID- 16966599
OWN - NLM
STAT- MEDLINE
DCOM- 20061214
LR  - 20220414
IS  - 0027-8424 (Print)
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Linking)
VI  - 103
IP  - 38
DP  - 2006 Sep 19
TI  - Ca2+/calmodulin-dependent protein kinase II (CaMKII) is activated by calmodulin 
      with two bound calciums.
PG  - 13968-73
AB  - Changes in synaptic strength that underlie memory formation in the CNS are 
      initiated by pulses of Ca2+ flowing through NMDA-type glutamate receptors into 
      postsynaptic spines. Differences in the duration and size of the pulses determine 
      whether a synapse is potentiated or depressed after repetitive synaptic activity. 
      Calmodulin (CaM) is a major Ca2+ effector protein that binds up to four Ca2+ 
      ions. CaM with bound Ca2+ can activate at least six signaling enzymes in the 
      spine. In fluctuating cytosolic Ca2+, a large fraction of free CaM is bound to 
      fewer than four Ca2+ ions. Binding to targets increases the affinity of CaM's 
      remaining Ca2+-binding sites. Thus, initial binding of CaM to a target may depend 
      on the target's affinity for CaM with only one or two bound Ca2+ ions. To study 
      CaM-dependent signaling in the spine, we designed mutant CaMs that bind Ca2+ only 
      at the two N-terminal or two C-terminal sites by using computationally designed 
      mutations to stabilize the inactivated Ca2+-binding domains in the "closed" 
      Ca2+-free conformation. We have measured their interactions with CaMKII, a major 
      Ca2+/CaM target that mediates initiation of long-term potentiation. We show that 
      CaM with two Ca2+ ions bound in its C-terminal lobe not only binds to CaMKII with 
      low micromolar affinity but also partially activates kinase activity. Our results 
      support the idea that competition for binding of CaM with two bound Ca2+ ions may 
      influence significantly the outcome of local Ca2+ signaling in spines and, 
      perhaps, in other signaling pathways.
FAU - Shifman, Julia M
AU  - Shifman JM
AD  - Division of Biology and Howard Hughes Medical Institute, California Institute of 
      Technology, Pasadena, CA 91125, USA.
FAU - Choi, Mee H
AU  - Choi MH
FAU - Mihalas, Stefan
AU  - Mihalas S
FAU - Mayo, Stephen L
AU  - Mayo SL
FAU - Kennedy, Mary B
AU  - Kennedy MB
LA  - eng
GR  - P01 NS044306-01A10003/NS/NINDS NIH HHS/United States
GR  - P01 NS044306-050003/NS/NINDS NIH HHS/United States
GR  - NS44306/NS/NINDS NIH HHS/United States
GR  - P01 NS044306-02/NS/NINDS NIH HHS/United States
GR  - P01 NS044306-040003/NS/NINDS NIH HHS/United States
GR  - P01 NS044306-03/NS/NINDS NIH HHS/United States
GR  - P01 NS044306-05/NS/NINDS NIH HHS/United States
GR  - P01 NS044306-02S1/NS/NINDS NIH HHS/United States
GR  - P01 NS044306-04/NS/NINDS NIH HHS/United States
GR  - P01 NS044306-01A1/NS/NINDS NIH HHS/United States
GR  - P01 NS044306-020003/NS/NINDS NIH HHS/United States
GR  - P01 NS044306-030003/NS/NINDS NIH HHS/United States
GR  - P01 NS044306/NS/NINDS NIH HHS/United States
GR  - K25 NS047300/NS/NINDS NIH HHS/United States
GR  - NS047300/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20060911
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Calmodulin)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2)
RN  - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinases)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Calcium/*metabolism
MH  - Calcium Signaling/physiology
MH  - Calcium-Calmodulin-Dependent Protein Kinase Type 2
MH  - Calcium-Calmodulin-Dependent Protein Kinases/*metabolism
MH  - Calmodulin/chemistry/genetics/*metabolism
MH  - Computer Simulation
MH  - Enzyme Activation
MH  - Models, Molecular
MH  - Protein Binding
MH  - Protein Conformation
MH  - Protein Folding
MH  - Synapses/physiology
PMC - PMC1599897
COIS- The authors declare no conflict of interest.
EDAT- 2006/09/13 09:00
MHDA- 2006/12/15 09:00
PMCR- 2007/03/19
CRDT- 2006/09/13 09:00
PHST- 2006/09/13 09:00 [pubmed]
PHST- 2006/12/15 09:00 [medline]
PHST- 2006/09/13 09:00 [entrez]
PHST- 2007/03/19 00:00 [pmc-release]
AID - 0606433103 [pii]
AID - 3457 [pii]
AID - 10.1073/pnas.0606433103 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2006 Sep 19;103(38):13968-73. doi: 
      10.1073/pnas.0606433103. Epub 2006 Sep 11.