PMID- 38352446
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240222
DP  - 2024 Feb 2
TI  - A spatial model of autophosphorylation of CaMKII in a glutamatergic spine 
      suggests a network-driven kinetic mechanism for bistable changes in synaptic 
      strength.
LID - 2024.02.02.578696 [pii]
LID - 10.1101/2024.02.02.578696 [doi]
AB  - Activation of N-methyl-D-aspartate-type glutamate receptors (NMDARs) at synapses 
      in the CNS triggers changes in synaptic strength that underlie memory formation 
      in response to strong synaptic stimuli. The primary target of Ca(2+) flowing 
      through NMDARs is Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) which 
      forms dodecameric holoenzymes that are highly concentrated at the postsynaptic 
      site. Activation of CaMKII is necessary to trigger long-term potentiation of 
      synaptic strength (LTP), and is prolonged by autophosphorylation of subunits 
      within the holoenzyme. Here we use MCell4, an agent-based, stochastic, modeling 
      platform to model CaMKII holoenzymes placed within a realistic spine geometry. We 
      show how two mechanisms of regulation of CaMKII, 'Ca(2+)-calmodulin-trapping 
      (CaM-trapping)' and dephosphorylation by protein phosphatase-1 (PP1) shape the 
      autophosphorylation response during a repeated high-frequency stimulus. Our 
      simulation results suggest that autophosphorylation of CaMKII does not constitute 
      a bistable switch. Instead, prolonged but temporary, autophosphorylation of 
      CaMKII may contribute to a biochemical-network-based 'kinetic proof-reading" 
      mechanism that controls induction of synaptic plasticity.
FAU - Bartol, Thomas M
AU  - Bartol TM
AD  - The Salk Institute for Biological Studies, La Jolla, CA.
FAU - Ordyan, Mariam
AU  - Ordyan M
AD  - The Salk Institute for Biological Studies, La Jolla, CA.
FAU - Sejnowski, Terrence J
AU  - Sejnowski TJ
AD  - The Salk Institute for Biological Studies, La Jolla, CA.
FAU - Rangamani, Padmini
AU  - Rangamani P
AUID- ORCID: 0000-0001-5953-4347
AD  - Department of Mechanical and Aerospace Engineering, University of California San 
      Diego, La Jolla, CA.
FAU - Kennedy, Mary B
AU  - Kennedy MB
AD  - Department of Biology and Biological Engineering, California Institute of 
      Technology, Pasadena, CA.
LA  - eng
GR  - P41 GM103712/GM/NIGMS NIH HHS/United States
GR  - R01 DA030749/DA/NIDA NIH HHS/United States
GR  - R01 MH115456/MH/NIMH NIH HHS/United States
GR  - R01 MH129066/MH/NIMH NIH HHS/United States
PT  - Preprint
DEP - 20240202
PL  - United States
TA  - bioRxiv
JT  - bioRxiv : the preprint server for biology
JID - 101680187
PMC - PMC10862815
EDAT- 2024/02/14 06:43
MHDA- 2024/02/14 06:44
PMCR- 2024/02/13
CRDT- 2024/02/14 03:53
PHST- 2024/02/14 06:43 [pubmed]
PHST- 2024/02/14 06:44 [medline]
PHST- 2024/02/14 03:53 [entrez]
PHST- 2024/02/13 00:00 [pmc-release]
AID - 2024.02.02.578696 [pii]
AID - 10.1101/2024.02.02.578696 [doi]
PST - epublish
SO  - bioRxiv [Preprint]. 2024 Feb 2:2024.02.02.578696. doi: 10.1101/2024.02.02.578696.