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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
Author(s) -
Woo Newton H.,
Abel Ted,
Nguyen Peter V.
Publication year - 2002
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1046/j.1460-9568.2002.02260.x
Subject(s) - long term potentiation , protein kinase a , phosphatase , forskolin , ltp induction , okadaic acid , adenylyl cyclase , microbiology and biotechnology , chemistry , protein phosphatase 1 , activator (genetics) , kinase , biology , biochemistry , phosphorylation , signal transduction , receptor
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.