Elucidating mechanisms regulating neuronal survival and plasticity is relevant for understanding normal learning and memory as well as cognitive impairments in mental retardation, aging and Alzheimer's. Influx of calcium ions (Ca2+) through L-type voltage-gated calcium channels (LTCCs) can influence long-term changes in synaptic plasticity and neuronal survival by turning on and off gene transcription in the nucleus. While it is known that signaling very near the site of Ca2+ influx is required for regulation of both LTCC activity and gene expression, molecular mechanisms that organize channel proximal signals and transduce them to the nucleus are largely unknown. One important pathway by which LTCC activity in neurons is regulated involves b-adrenergic receptor-mediated stimulation of cAMP production by adenylyl cyclase and activation of the kinase PKA. Previous studies in the heart suggest that efficient regulation of LTCC activity by PKA requires phosphorylation of the channel protein and localization of PKA near the channel through binding to A-kinase-anchoring proteins (AKAP). However, little is known about the roles of AKAPs or the opposing actions of protein phosphatases in neuronal LTCC regulation. In postsynaptic neurons one AKAP that may play a key role in regulating LTCC phosphorylation and signaling to transcription factors in the nucleus is AKAP79/150. Our overall hypothesis is that AKAP79/150 targets PKA and CaN to LTCCs to bi-directionally regulate channel activity and signaling to the nucleus. We will test this hypothesis in the context of a model in which anchored CaN strongly opposes cAMP-PKA regulation of the channel currents to function as a Ca2+ negative feedback mechanism. In addition, we will explore a novel role for dynamic anchoring of PKA and CaN to AKAP79/150 in these plasma membrane localized Ca2+ signaling events that also control downstream activation of NFAT and CREB transcription factors. Thus, our studies will characterize a novel molecular assembly that coordinates plasma membrane LTCC Ca2+ signaling to regulate both local and distal responses that are important in neuronal plasticity. We will use biochemical, cell biological and electrophysiological approaches in HEK-293 cells and hippocampal neurons to study AKAP79/150-LTCC regulation:
(Aim 1) Molecular and functional characterization of a direct interaction between AKAP79/150 and the LTCC CaV1.2 in neuronal channel regulation;
(Aim 2) Role of dynamic PKA and CaN anchoring to AKAP79/150 in neuronal LTCC regulation;
(Aim 3) Role of the AKAP79/150 channel-associated signaling complex in regulating neuronal LTCC excitation-transcription coupling.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
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Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
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Asanuma, Chiiko
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University of Colorado Denver
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Dittmer, Philip J; Wild, Angela R; Dell'Acqua, Mark L et al. (2017) STIM1 Ca2+ Sensor Control of L-type Ca2+-Channel-Dependent Dendritic Spine Structural Plasticity and Nuclear Signaling. Cell Rep 19:321-334
Dittmer, Philip J; Dell'Acqua, Mark L; Sather, William A (2014) Ca2+/calcineurin-dependent inactivation of neuronal L-type Ca2+ channels requires priming by AKAP-anchored protein kinase A. Cell Rep 7:1410-1416
Nystoriak, Matthew A; Nieves-CintrĂ³n, Madeline; Nygren, Patrick J et al. (2014) AKAP150 contributes to enhanced vascular tone by facilitating large-conductance Ca2+-activated K+ channel remodeling in hyperglycemia and diabetes mellitus. Circ Res 114:607-15
Murphy, Jonathan G; Sanderson, Jennifer L; Gorski, Jessica A et al. (2014) AKAP-anchored PKA maintains neuronal L-type calcium channel activity and NFAT transcriptional signaling. Cell Rep 7:1577-1588
Freund, Ronald K (2012) Commentary: How ethanol short-circuits the cerebellum-actions on Golgi cells in freely-moving animals. Alcohol Clin Exp Res 36:1837-9
Brandao, Katherine E; Dell'Acqua, Mark L; Levinson, S Rock (2012) A-kinase anchoring protein 150 expression in a specific subset of TRPV1- and CaV 1.2-positive nociceptive rat dorsal root ganglion neurons. J Comp Neurol 520:81-99
Li, Huiming; Pink, Matthew D; Murphy, Jonathan G et al. (2012) Balanced interactions of calcineurin with AKAP79 regulate Ca2+-calcineurin-NFAT signaling. Nat Struct Mol Biol 19:337-45
Oliveria, Seth F; Dittmer, Philip J; Youn, Dong-ho et al. (2012) Localized calcineurin confers Ca2+-dependent inactivation on neuronal L-type Ca2+ channels. J Neurosci 32:15328-37
Lin, Lin; Sun, Wei; Kung, Faith et al. (2011) AKAP79/150 impacts intrinsic excitability of hippocampal neurons through phospho-regulation of A-type K+ channel trafficking. J Neurosci 31:1323-32
Sanderson, Jennifer L; Dell'Acqua, Mark L (2011) AKAP signaling complexes in regulation of excitatory synaptic plasticity. Neuroscientist 17:321-36