Abstract
CaMKIIα plays an essential role in decoding Ca2+ signaling in spines by acting as a leaky Ca2+ integrator with the time constant of several seconds. However, the mechanism by which CaMKIIα integrates Ca2+ signals remains elusive. Here, we imaged CaMKIIα-CaM association in single dendritic spines using a new FRET sensor and two-photon fluorescence lifetime imaging. In response to a glutamate uncaging pulse, CaMKIIα-CaM association increases in ~0.1 s and decays over ~3 s. During repetitive glutamate uncaging, which induces spine structural plasticity, CaMKIIα-CaM association did not show further increase but sustained at a constant level. Since CaMKIIα activity integrates Ca2+ signals over ~10 s under this condition, the integration of Ca2+ signal by CaMKIIα during spine structural plasticity is largely due to Ca2+/CaM-independent, autonomous activity. Based on these results, we propose a simple kinetic model of CaMKIIα activation in dendritic spines.
Highlights
CaMKIIα plays an essential role in decoding Ca2+ signaling in spines by acting as a leaky Ca2+ integrator with the time constant of several seconds
To measure the association of CaMKIIα with CaM, we developed a fluorescence resonance energy transfer (FRET)-based biosensor made of monomeric EGFPCaMKIIα and mCherry-CaM (Fig. 1a)[19]
This suggests that CaMindependent CaMKIIα activation, i.e., autonomous activation, is the dominant mechanism that causes the accumulation of CaMKIIα activity during the induction of structural LTP (sLTP)
Summary
CaMKIIα plays an essential role in decoding Ca2+ signaling in spines by acting as a leaky Ca2+ integrator with the time constant of several seconds. It is known that phosphorylation at Thr[286] causes an enhancement in binding affinity to Ca2+/CaM7,12 as well as induces a Ca2+/CaM-independent, autonomous kinase activity state[13,14] This autonomous activity of CaMKIIα is thought to be important for the induction and the maintenance of LTP14. Camuiα measures the conformation change of CaMKIIα associated with its activation by both Ca2+/CaM binding and Thr[286] autophosphorylation[6,17] Previous studies using this sensor suggest that the optimal integration of Ca2+ signals by CaMKIIα requires Thr[286] autophosphorylation, suggesting that autonomous activity may play an important role in this process[6,10]. If an autonomous state of CaMKIIα exists in the stimulated spines, and if so, how much this state contributes to CaMKIIα activation remains elusive
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