AKAP150-anchored PKA activity is important for LTD during its induction phase.
Protein kinase A (PKA) is thought to tonically maintain an enhanced level of postsynaptic AMPA receptor responses. Injection of PKA inhibitory peptides leads to a run-down of AMPA receptor responses and prevents long-term depression (LTD). This run-down of AMPA receptor activity was proposed to occlude a further reduction that would otherwise constitute LTD. PKA is recruited to postsynaptic sites by the A kinase anchor protein AKAP150. We found that LTD was strongly impaired in acute hippocampal slices from 2-week-old mice in which the PKA binding site on AKAP150 had been genetically deleted (D36 mice). However, basal postsynaptic AMPA and NMDA receptor activity was indistinguishable between D36 and WT mice. During extracellular recordings of field EPSPs and during intracellular recording of EPSCs from hippocampal slices from WT mice, H-89 and KT5720, two structurally different PKA inhibitors, inhibited LTD by more than 70% without affecting basal synaptic transmission or basal phosphorylation of serine 845 on GluR1. Collectively our data indicate that AKAP150-anchored PKA activity is required to induce LTD and not merely to maintain a tonically heightened activity level of AMPA receptors as proposed earlier.
Lu
Yuan
Y
Department of Pharmacology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, 51 Newton Road, Iowa City, IA 52242-1109, USA.
Zhang
Mingxu
M
Lim
Indra A
IA
Hall
Duane D
DD
Allen
Margaret
M
Medvedeva
Yuliya
Y
McKnight
G Stanley
GS
Usachev
Yuriy M
YM
Hell
Johannes W
JW
D054758:A Kinase Anchor Proteins / Q000235:genetics*; D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017353:Gene Deletion; D006624:Hippocampus / Q000166:cytology / Q000502:physiology; D007546:Isoquinolines / Q000494:pharmacology; D036881:Long-Term Synaptic Depression / Q000235:genetics* / Q000502:physiology*; D008297:Male; D051379:Mice; D011758:Pyrroles / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
D054758:A Kinase Anchor Proteins; C520665:Akap5 protein, mouse; D002227:Carbazoles; D007546:Isoquinolines; D011758:Pyrroles; D013449:Sulfonamides; C057416:KT 5720; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide