AKAP79/150 anchoring of calcineurin controls neuronal L-type Ca2+ channel activity and nuclear signaling.
Neuronal L-type calcium channels contribute to dendritic excitability and activity-dependent changes in gene expression that influence synaptic strength. Phosphorylation-mediated enhancement of L-type channels containing the CaV1.2 pore-forming subunit is promoted by A-kinase anchoring proteins (AKAPs) that target cAMP-dependent protein kinase (PKA) to the channel. Although PKA increases L-type channel activity in dendrites and dendritic spines, the mechanism of enhancement in neurons remains poorly understood. Here, we show that CaV1.2 interacts directly with AKAP79/150, which binds both PKA and the Ca2+/calmodulin-activated phosphatase calcineurin (CaN). Cotargeting of PKA and CaN by AKAP79/150 confers bidirectional regulation of L-type current amplitude in transfected HEK293 cells and hippocampal neurons. However, anchored CaN dominantly suppresses PKA enhancement of the channel. Additionally, activation of the transcription factor NFATc4 via local Ca2+ influx through L-type channels requires AKAP79/150, suggesting that this signaling complex promotes neuronal L channel signaling to the nucleus through NFATc4.
Oliveria
Seth F
SF
Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Dell'Acqua
Mark L
ML
Sather
William A
WA
D054758:A Kinase Anchor Proteins; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D019556:COS Cells; D019703:Calcineurin / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D002460:Cell Line; D002522:Chlorocebus aethiops; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D016350:Leucine Zippers / Q000502:physiology; D050778:NFATC Transcription Factors / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009685:Nuclear Envelope / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology
D054758:A Kinase Anchor Proteins; C487775:AKAP5 protein, human; D048868:Adaptor Proteins, Signal Transducing; C415703:Akap5 protein, rat; D020746:Calcium Channels, L-Type; C419385:L-type calcium channel alpha(1C); D050778:NFATC Transcription Factors; D017868:Cyclic AMP-Dependent Protein Kinases; D019703:Calcineurin