Genetic and pharmacological demonstration of a role for cyclic AMP-dependent protein kinase-mediated suppression of protein phosphatases in gating the expression of late LTP.
Protein kinases and phosphatases play antagonistic roles in regulating hippocampal long-term potentiation (LTP), with kinase inhibition and phosphatase activation both impairing LTP. The late phase of LTP (L-LTP) requires activation of cAMP-dependent protein kinase (PKA) for its full expression. One way in which PKA may critically modulate L-LTP is by relieving an inhibitory constraint imposed by protein phosphatases. Using mutant PKA mice [R(AB) transgenic mice] that have genetically reduced hippocampal PKA activity, we show that deficient L-LTP in area CA1 of mutant hippocampal slices is rescued by acute application of two inhibitors of protein phosphatase-1 and protein phosphatase-2A (PP1/2A) (okadaic acid and calyculin A). Furthermore, synaptic facilitation induced by forskolin, an adenylyl cyclase activator, was impaired in R(AB) transgenics and was also rescued by a PP1/2A inhibitor in mutant slices. Inhibition of PP1/2A did not affect early LTP (E-LTP) or basal synaptic transmission in mutant and wildtype slices. Our data show that genetic inhibition of PKA impairs L-LTP by reducing PKA-mediated suppression of PP1/2A.
Woo
Newton H
NH
Department of Physiology, University of Alberta School of Medicine, Edmonton, Alberta, T6G 2H7, Canada.
Abel
Ted
T
Nguyen
Peter V
PV
D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D004594:Electrophysiology; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D017774:Long-Term Potentiation; D008297:Male; D008387:Marine Toxins; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D019319:Okadaic Acid / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D009435:Synaptic Transmission
D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D008387:Marine Toxins; D010080:Oxazoles; D005576:Colforsin; D019319:Okadaic Acid; C059041:calyculin A; D017868:Cyclic AMP-Dependent Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2