CAKbeta/Pyk2 kinase is a signaling link for induction of long-term potentiation in CA1 hippocampus.
Long-term potentiation (LTP) is an activity-dependent enhancement of synaptic efficacy, considered a model of learning and memory. The biochemical cascade producing LTP requires activation of Src, which upregulates the function of NMDA receptors (NMDARs), but how Src becomes activated is unknown. Here, we show that the focal adhesion kinase CAKbeta/Pyk2 upregulated NMDAR function by activating Src in CA1 hippocampal neurons. Induction of LTP was prevented by blocking CAKbeta/Pyk2, and administering CAKbeta/Pyk2 intracellularly mimicked and occluded LTP. Tyrosine phosphorylation of CAKbeta/Pyk2 and its association with Src was increased by stimulation that produced LTP. Finally, CAKbeta/Pyk2-stimulated enhancement of synaptic AMPA responses was prevented by blocking NMDARS, chelating intracellular Ca(2+), or blocking Src. Thus, activating CAKbeta/Pyk2 is required for inducing LTP and may depend upon downstream activation of Src to upregulate NMDA receptors.
Programmes in Brain and, Behaviour & Cell Biology, Hospital for Sick Children, Ontario, M5G 1X8, Toronto, Canada.
Y
Y
Huang
W
W
Lu
D W
DW
Ali
K A
KA
Pelkey
G M
GM
Pitcher
Y M
YM
Lu
H
H
Aoto
J C
JC
Roder
T
T
Sasaki
M W
MW
Salter
J F
JF
MacDonald
D000818:Animals; D051418:Focal Adhesion Kinase 2; D006624:Hippocampus / Q000502:physiology; D017774:Long-Term Potentiation / Q000502:physiology*; D008297:Male; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D017966:Pyramidal Cells / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology; D019061:src-Family Kinases / Q000378:metabolism / Q000502:physiology*
D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D011505:Protein-Tyrosine Kinases; D051418:Focal Adhesion Kinase 2; C496054:Ptk2b protein, rat; D019061:src-Family Kinases