AKAP-anchored PKA maintains neuronal L-type calcium channel activity and NFAT transcriptional signaling.
L-type voltage-gated Ca2+ channels (LTCC) couple neuronal excitation to gene transcription. LTCC activity is elevated by the cyclic AMP (cAMP)-dependent protein kinase (PKA) and depressed by the Ca2+-dependent phosphatase calcineurin (CaN), and both enzymes are localized to the channel by A-kinase anchoring protein 79/150 (AKAP79/150). AKAP79/150 anchoring of CaN also promotes LTCC activation of transcription through dephosphorylation of the nuclear factor of activated T cells (NFAT). We report here that the basal activity of AKAP79/150-anchored PKA maintains neuronal LTCC coupling to CaN-NFAT signaling by preserving LTCC phosphorylation in opposition to anchored CaN. Genetic disruption of AKAP-PKA anchoring promoted redistribution of the kinase out of postsynaptic dendritic spines, profound decreases in LTCC phosphorylation and Ca2+ influx, and impaired NFAT movement to the nucleus and activation of transcription. Thus, LTCC-NFAT transcriptional signaling in neurons requires precise organization and balancing of PKA and CaN activities in the channel nanoenvironment, which is only made possible by AKAP79/150 scaffolding.
Department of Pharmacology, Anschutz Medical Campus, University of Colorado School of Medicine, Aurora, CO 80045, USA; Neuroscience Program, Anschutz Medical Campus, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Jonathan G
JG
Murphy
Department of Pharmacology, Anschutz Medical Campus, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Jennifer L
JL
Sanderson
Department of Pharmacology, Anschutz Medical Campus, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Jessica A
JA
Gorski
Howard Hughes Medical Institute, University of Washington School of Medicine, Seattle, WA 98195, USA; Department of Pharmacology, University of Washington School of Medicine, Seattle, WA 98195, USA.
John D
JD
Scott
Department of Pharmacology, University of Washington School of Medicine, Seattle, WA 98195, USA.
William A
WA
Catterall
Department of Pharmacology, Anschutz Medical Campus, University of Colorado School of Medicine, Aurora, CO 80045, USA; Neuroscience Program, Anschutz Medical Campus, University of Colorado School of Medicine, Aurora, CO 80045, USA.
William A
WA
Sather
Department of Pharmacology, Anschutz Medical Campus, University of Colorado School of Medicine, Aurora, CO 80045, USA; Neuroscience Program, Anschutz Medical Campus, University of Colorado School of Medicine, Aurora, CO 80045, USA. Electronic address: mark.dellacqua@ucdenver.edu.
Mark L
ML
Dell'Acqua
D054758:A Kinase Anchor Proteins / Q000378:metabolism*; D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D049229:Dendritic Spines / Q000378:metabolism* / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D015398:Signal Transduction; D015533:Transcriptional Activation
D054758:A Kinase Anchor Proteins; D020746:Calcium Channels, L-Type; D050778:NFATC Transcription Factors; D017868:Cyclic AMP-Dependent Protein Kinases; D019703:Calcineurin