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The Journal of Neuroscience, April 15, 2002, 22(8):3044-3051
Regulation of GluR1 by the A-Kinase Anchoring Protein 79 (AKAP79) Signaling Complex Shares Properties with Long-Term
Depression
Steven J.
Tavalin1,
Marcie
Colledge1,
Johannes
W.
Hell2,
Lorene K.
Langeberg1,
Richard L.
Huganir3, and
John D.
Scott1
1 Howard Hughes Medical Institute, Vollum Institute,
Oregon Health Sciences University, Portland, Oregon 97201, 2 Department of Pharmacology, University of Iowa, Iowa
City, Iowa 52242, and 3 Howard Hughes Medical Institute,
Department of Neuroscience, The Johns Hopkins University School of
Medicine, Baltimore, Maryland 21205
Second messengers regulate synaptic plasticity by influencing the
balance between kinase and phosphatase activity. One target of this
balance is the phosphorylation state of the AMPA receptor glutamate
receptor 1 (GluR1) subunit. Hippocampal long-term depression (LTD) is a
calcium-dependent downregulation of synaptic AMPA receptor currents
associated with dephosphorylation of Ser845, a cAMP-dependent protein
kinase (PKA) site on GluR1. Recruitment of kinases and phosphatases to
the AMPA receptor might enable modulation of AMPA receptor function.
The neuronal A-kinase anchoring protein AKAP79/150 interacts with PKA
and the calcium-dependent protein phosphatase PP2B and is linked
to the AMPA receptor GluR1 subunit by synapse-associated protein 97 (SAP97), a membrane-associated guanylate kinase family protein.
Here we demonstrate that AKAP79 not only promotes basal phosphorylation
of Ser845 but also confers a calcium- and PP2B-mediated downregulation
to GluR1 receptor currents. This AKAP79-dependent downregulation is
contingent on the local presence of PKA, Ser845 of GluR1, and a PDZ
(postsynaptic density 95/Discs large/zona occludens 1)-domain
interaction between GluR1 and SAP97, all of which support basal
phosphorylation of the receptor. These findings suggest that the AKAP79
signaling complex is sufficient to couple intracellular calcium levels
to the PKA phosphorylation state of GluR1. Thus, the integration of
intracellular signals relevant for LTD may be transduced to GluR1 by
the AKAP79 signaling complex.
Key words:
AKAP79; kinase; phosphatase; cAMP; calcium; AMPA
receptor; synaptic plasticity
Copyright © 2002 Society for Neuroscience 0270-6474/02/2283044-08$05.00/0
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