Control of excitatory synaptic transmission by C-terminal Src kinase.
The induction of long-term potentiation at CA3-CA1 synapses is caused by an N-methyl-d-aspartate (NMDA) receptordependent accumulation of intracellular Ca(2+), followed by Src family kinase activation and a positive feedback enhancement of NMDA receptors (NMDARs). Nevertheless, the amplitude of baseline transmission remains remarkably constant even though low frequency stimulation is also associated with an NMDAR-dependent influx of Ca(2+) into dendritic spines. We show here that an interaction between C-terminal Src kinase (Csk) and NMDARs controls the Src-dependent regulation of NMDAR activity. Csk associates with the NMDAR signaling complex in the adult brain, inhibiting the Src-dependent potentiation of NMDARs in CA1 neurons and attenuating the Src-dependent induction of long-term potentiation. Csk associates directly with Src-phosphorylated NR2 subunits in vitro. An inhibitory antibody for Csk disrupts this physical association, potentiates NMDAR mediated excitatory postsynaptic currents, and induces long-term potentiation at CA3-CA1 synapses. Thus, Csk serves to maintain the constancy of baseline excitatory synaptic transmission by inhibiting Src kinase-dependent synaptic plasticity in the hippocampus.
Xu
Jindong
J
Faculty of Dentistry, University of Toronto, Toronto, Ontario M5G 1G6, Canada.
Weerapura
Manjula
M
Ali
Mohammad K
MK
Jackson
Michael F
MF
Li
Hongbin
H
Lei
Gang
G
Xue
Sheng
S
Kwan
Chun L
CL
Manolson
Morris F
MF
Yang
Kai
K
Macdonald
John F
JF
Yu
Xian-Min
XM
D000818:Animals; D001921:Brain / Q000378:metabolism; D019556:COS Cells; D000081247:CSK Tyrosine-Protein Kinase; D002522:Chlorocebus aethiops; D003712:Dendrites / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D017774:Long-Term Potentiation; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D013347:Subcellular Fractions; D009435:Synaptic Transmission; D019061:src-Family Kinases / Q000378:metabolism*
D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human