Mutations in AKAP5 disrupt dendritic signaling complexes and lead to electrophysiological and behavioral phenotypes in mice.
AKAP5 (also referred to as AKAP150 in rodents and AKAP79 in humans) is a scaffolding protein that is highly expressed in neurons and targets a variety of signaling molecules to dendritic membranes. AKAP5 interacts with PKA holoenzymes containing RIIalpha or RIIbeta as well as calcineurin (PP2B), PKC, calmodulin, adenylyl cyclase type V/VI, L-type calcium channels, and beta-adrenergic receptors. AKAP5 has also been shown to interact with members of the MAGUK family of PSD-scaffolding proteins including PSD95 and SAP97 and target signaling molecules to receptors and ion channels in the postsynaptic density (PSD). We created two lines of AKAP5 mutant mice: a knockout of AKAP5 (KO) and a mutant that lacks the PKA binding domain of AKAP5 (D36). We find that PKA is delocalized in both the hippocampus and striatum of KO and D36 mice indicating that other neural AKAPs cannot compensate for the loss of PKA binding to AKAP5. In AKAP5 mutant mice, a significant fraction of PKA becomes localized to dendritic shafts and this correlates with increased binding to microtubule associated protein-2 (MAP2). Electrophysiological and behavioral analysis demonstrated more severe deficits in both synaptic plasticity and operant learning in the D36 mice compared with the complete KO animals. Our results indicate that the targeting of calcineurin or other binding partners of AKAP5 in the absence of the balancing kinase, PKA, leads to a disruption of synaptic plasticity and results in learning and memory defects.
Weisenhaus
Michael
M
Department of Pharmacology, University of Washington School of Medicine, Seattle, Washington, United States of America.
Allen
Margaret L
ML
Yang
Linghai
L
Lu
Yuan
Y
Nichols
C Blake
CB
Su
Thomas
T
Hell
Johannes W
JW
McKnight
G Stanley
GS
D054758:A Kinase Anchor Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D000818:Animals; D001665:Binding Sites; D003342:Corpus Striatum; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism / Q000473:pathology*; D055724:Electrophysiological Phenomena / Q000235:genetics*; D006624:Hippocampus; D007859:Learning Disabilities / Q000209:etiology / Q000235:genetics*; D008569:Memory Disorders / Q000209:etiology / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009473:Neuronal Plasticity; D011485:Protein Binding; D015398:Signal Transduction
D054758:A Kinase Anchor Proteins; C520665:Akap5 protein, mouse; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D017868:Cyclic AMP-Dependent Protein Kinases