APPL1 gates long-term potentiation through its plekstrin homology domain
J Cell Sci. 2016-06-02; 129(14): 2793-2803
DOI: 10.1242/jcs.183475
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Hippocampal synaptic plasticity involves both membrane trafficking events and
intracellular signaling, but how these are coordinated is far from clear. The
endosomal transport of glutamate receptors in and out of the postsynaptic
membrane responds to multiple signaling cascades triggered by synaptic activity.
In this work, we have identified adaptor protein containing a plekstrin homology
domain, phosphotyrosine-binding domain and leucine zipper motif 1 (APPL1) as a
crucial element linking trafficking and signaling during synaptic plasticity. We
show that APPL1 knockdown specifically impairs PI3K-dependent forms of synaptic
plasticity, such as long-term potentiation (LTP) and
metabotropic-glutamate-receptor-dependent long-term depression (mGluR-LTD).
Indeed, we demonstrate that APPL1 is required for the activation of the
phosphatidylinositol triphosphate (PIP3) pathway in response to LTP induction.
This requirement can be bypassed by membrane localization of PI3K and is related
to phosphoinositide binding. Interestingly, inhibitors of PDK1 (also known as
PDPK1) and Akt have no effect on LTP expression. Therefore, we conclude that
APPL1 gates PI3K activation at the plasma membrane upon LTP induction, which is
then relayed by downstream PIP3 effectors that are different from PDK1 and Akt.
© 2016. Published by The Company of Biologists Ltd.