Loss of AKAP150 perturbs distinct neuronal processes in mice.
A-Kinase Anchoring Proteins (AKAPs) ensure the fidelity of second messenger signaling events by directing protein kinases and phosphatases toward their preferred substrates. AKAP150 brings protein kinase A (PKA), the calcium/calmodulin dependent phosphatase PP2B and protein kinase C (PKC) to postsynaptic membranes where they facilitate the phosphorylation dependent modulation of certain ion channels. Immunofluorescence and electrophysiological recordings were combined with behavioral analyses to assess whether removal of AKAP150 by gene targeting in mice changes the signaling environment to affect excitatory and inhibitory neuronal processes. Mislocalization of PKA in AKAP150 null hippocampal neurons alters the bidirectional modulation of postsynaptic AMPA receptors with concomitant changes in synaptic transmission and memory retention. AKAP150 null mice also exhibit deficits in motor coordination and strength that are consistent with a role for the anchoring protein in the cerebellum. Loss of AKAP150 in sympathetic cervical ganglion (SCG) neurons reduces muscarinic suppression of inhibitory M currents and provides these animals with a measure of resistance to seizures induced by the non-selective muscarinic agonist pilocarpine. These studies argue that distinct AKAP150-enzyme complexes regulate context-dependent neuronal signaling events in vivo.
Tunquist
Brian J
BJ
Howard Hughes Medical Institute, Oregon Health and Science University, 3181 South West Sam Jackson Park Road, Portland, Oregon 97239, USA.
Hoshi
Naoto
N
Guire
Eric S
ES
Zhang
Fang
F
Mullendorff
Karin
K
Langeberg
Lorene K
LK
Raber
Jacob
J
Scott
John D
JD
D054758:A Kinase Anchor Proteins / Q000172:deficiency*; D000818:Animals; D002531:Cerebellum / Q000166:cytology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D019957:Motor Skills Disorders / Q000209:etiology; D018721:Muscarinic Agonists / Q000494:pharmacology; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000502:physiology*; D018091:Receptors, AMPA / Q000378:metabolism; D012640:Seizures; D015398:Signal Transduction / Q000502:physiology
D054758:A Kinase Anchor Proteins; C520665:Akap5 protein, mouse; D018721:Muscarinic Agonists; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; D017868:Cyclic AMP-Dependent Protein Kinases