Reciprocal Activation within a Kinase-Effector Complex Underlying Persistence of Structural LTP

Neuron. 2019 Jun 19;102(6):1199-1210.e6. doi: 10.1016/j.neuron.2019.04.012. Epub 2019 May 8.


Long-term synaptic plasticity requires a mechanism that converts short Ca2+ pulses into persistent biochemical signaling to maintain changes in the synaptic structure and function. Here, we present a novel mechanism of a positive feedback loop, formed by a reciprocally activating kinase-effector complex (RAKEC) in dendritic spines, enabling the persistence and confinement of a molecular memory. We found that stimulation of a single spine causes the rapid formation of a RAKEC consisting of CaMKII and Tiam1, a Rac-GEF. This interaction is mediated by a pseudo-autoinhibitory domain on Tiam1, which is homologous to the CaMKII autoinhibitory domain itself. Therefore, Tiam1 binding results in constitutive CaMKII activation, which in turn persistently phosphorylates Tiam1. Phosphorylated Tiam1 promotes stable actin-polymerization through Rac1, thereby maintaining the structure of the spine during LTP. The RAKEC can store biochemical information in small subcellular compartments, thus potentially serving as a general mechanism for prolonged and compartmentalized signaling.

Keywords: Ca(2+)/calmodulin-dependent protein kinase II; Rho family small GTPase; actin cytoskeleton; dendritic spine; guanine-nucleotide exchange factor; long-term potentiation; pseudo-autoinhibitory domain; reciprocally activating kinase-effector complex (RAKEC); synaptic plasticity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism*
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism*
  • Dendritic Spines / metabolism*
  • Dendritic Spines / ultrastructure
  • Feedback, Physiological
  • Guanine Nucleotide Exchange Factors / metabolism
  • Hippocampus / cytology
  • Long-Term Potentiation / drug effects
  • Long-Term Potentiation / physiology*
  • Microscopy, Confocal
  • Neurons / metabolism*
  • Neurons / ultrastructure
  • Phosphorylation
  • Polymerization
  • Pyrones / pharmacology
  • Quinolines / pharmacology
  • Rats
  • T-Lymphoma Invasion and Metastasis-inducing Protein 1 / metabolism*
  • rac1 GTP-Binding Protein / antagonists & inhibitors
  • rac1 GTP-Binding Protein / metabolism*


  • Actins
  • EHT 1864
  • Guanine Nucleotide Exchange Factors
  • Pyrones
  • Quinolines
  • T-Lymphoma Invasion and Metastasis-inducing Protein 1
  • Tiam1 protein, rat
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Rac1 protein, rat
  • rac1 GTP-Binding Protein