CaMKII Autophosphorylation Switch

Stimulus Train

Stimulation frequency 10 Hz

Ca²⁺ influx per pulse 0.9 µM

Phosphatase (PP1) activity 1.0×

Molecular Switch State

DephosphorylatedAutophosphorylated

— basal —

[Ca²⁺] spine

0.05 µM

CaMKII-P fraction

20%

Synaptic weight

100%

Pulses delivered

How it works

CaMKII (Ca²⁺/calmodulin-dependent protein kinase II) forms a 12-subunit holoenzyme at the postsynaptic density. When intracellular Ca²⁺ rises (via NMDA-receptor Ca²⁺ influx), Ca²⁺/calmodulin binds a subunit and activates it; an active subunit can then trans-autophosphorylate its neighbor at Thr286, locking that neighbor active even after Ca²⁺/CaM unbinds. This positive feedback, opposed by a phosphatase (PP1) that itself saturates at high phospho-CaMKII, produces a classic bistable biochemical switch (Lisman 1985; Zhabotinsky 2000):

dCa/dt = -Ca/τ_Ca + Σ pulses(t)
C(Ca)  = Ca⁴ / (Ca⁴ + K_act⁴)      (cooperative Ca²⁺/CaM binding, Hill n=4)
dP/dt  = C(Ca)·(k0 + k1·P)·(1-P) - kpp·P/(Kpp+P)

The autocatalytic term k1·P·(1−P) is the neighbor-phosphorylates-neighbor step; the phosphatase term is deliberately Michaelis–Menten (saturating at small Kpp), which is what makes the P=0 and P=1 branches both stable — the "zero-order ultrasensitivity" mechanism. Once Ca²⁺ input pushes P past the unstable middle branch, the switch flips and stays flipped after Ca²⁺ returns to baseline, because the autophosphorylated state is self-sustaining. That persistence is the leading molecular candidate for how a synapse stores a memory trace across LTP (switch ON, more phospho-CaMKII → more AMPA receptors inserted → stronger synapse) and LTD (switch OFF → AMPA receptors removed → weaker synapse).

Stimulation frequency — higher frequency means less time between pulses for Ca²⁺ to decay (τ_Ca≈80 ms), so Ca²⁺ summates to a higher plateau — this is the real biophysical reason high-frequency tetanic stimulation favors LTP and low-frequency stimulation favors LTD.
Ca²⁺ influx per pulse — models NMDA receptor conductance (voltage-dependent Mg²⁺ block relief); larger pulses reach the switching threshold in fewer stimuli.
Phosphatase activity — models the PP1/calcineurin balance; raising it shifts the threshold and can pull an already-ON switch back OFF, which is exactly how LTD reverses prior potentiation.
Synaptic weight readout — a simple linear proxy W = 50% + 100%·P, standing in for AMPA-receptor-mediated conductance, since phospho-CaMKII promotes AMPAR trafficking into the postsynaptic density.

Dephosphorylated subunit Phosphorylated (Thr286) subunit AMPA receptor

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