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Calcium-Calmodulin Kinase in Learning and Memory

The neural mechanism of learning and memory has always been a hot topic for scientists. In 1971, Giacobini proposed the theory of synaptic plasticity, which believed that the structure and number of synapses in the brain and the transmission effect between synapses will change during the process of learning and memory. In 1973, Bliss discovered that tetanic stimulation could induce the facilitation of synaptic transmission that lasts more than 10 hours in anesthetized rabbits, which is long-term potentiation (LTP). In the early 1990s, Linch et al. found that animals' memory after behavioral training was always accompanied by the appearance of LTP, which was named learned LTP. Further research showed that LTP is widely present in the brain structure closely related to learning and memory activities. Later, through many experiments, scientists discovered a memory “molecular switch”, calcium/calmodulin-dependent protein kinase II (CaM kinase II or CaMKII). During learning, the enzyme is activated by phosphorylation and catalyzes autophosphorylation, so that the kinase can remain active for a long time after learning.

Introduction of CaMKII

CaMKII is a serine/threonine-specific protein kinase regulated by the Ca2+ /calmodulin complex. It is involved in many signaling cascades and is an important regulator in learning and memory. CaMKII plays an important role in Ca2+ homeostasis and reuptake in cardiomyocytes, transportation of chloride ion in epithelial cells, selection of positive T cell, and activation of CD8 T cell.

CaMKII gamma holoenzyme in its (A) closed and the (B) open conformations. Fig.1 CaMKII gamma holoenzyme in its (A) closed and the (B) open conformations.

  • Types

Specialized CaM kinases: such as myosin light chain kinase which involves smooth muscle contraction through phosphorylating myosin.

Multifunctional CaM kinases: involves transcription factor regulation, neurotransmitter secretion, and glycogen metabolism.

Isoforms Function
CaMK2A Major forms of CamKII, involves sustaining activation of CamKII at the postsynaptic density
CaMK2B As a targeting or docking module, Contain an autophosphorylation site at Thr287
CaMK2D Present in both neuronal and non-neuronal cell types, also found in many tumor cells
CaMK2G A crucial extracellular signal-regulated kinase in differentiated smooth muscle cells
  • Structure
Domain Characterization
Catalytic Domain The catalytic domain, containing several binding sites for ATP and other substrate-anchored proteins, functions to transfer a phosphate from ATP to serine or threonine residues in substances.
Autoinhibitory Domain Characterized by a pseudosubstrate site that can bind to the catalytic domain and inhibit its binding to phosphorylate proteins.
Variable Segment Associated with the various CaMKII isoforms.
Self-Association Domain Found at the C terminus and involves the assembly of the single proteins into large multimers

Function of CaMKII in LTP

In an excitatory synapse, the formation of LTP includes two stages, namely the early induction stage, and the late maintenance stage.

  • Induction of LTP

The increase of presynaptic glutamate transmitter release and enhancement of post-synaptic depolarization could activate the glutamate receptor-NMDA complex on the postsynaptic membrane. Ca2+ ions could enter the postsynaptic cell through the NMDA receptor. CaMKII can recognize the increased signals of Ca2+ ions and autophosphorylation occurs when the Ca2+ is continuously increased to a certain concentration, thereby forming a stable open state, and inducing a series of biochemical reactions related to Ca2+, finally inducing LTP.

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For Research Use Only. Not For Clinical Use.
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