AKAP79/150 Anchoring of Calcineurin Controls Neuronal L-Type Ca2+ Channel Activity and Nuclear Signaling

Abstract

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.

Calcium influx through L-type CaV1.2 Ca2+ channels regulates mandibular development

“…Second, expression of a constitutively active calcineurin was able to bypass the requirement for Ca 2+ influx through Ca V 1.2 ( Figure 6). It is intriguing that calcineurin is a part of the Ca V 1.2 macromolecular complex, having been shown to interact either directly with Ca V 1.2 (22) or through an A-kinase anchoring protein (23). The most likely target of activated calcineurin is NFAT.…”

Distinct Activation Properties of the Nuclear Factor of Activated T-cells (NFAT) Isoforms NFATc3 and NFATc4 in Neurons

“…For example, activation of L-type calcium channels by elevating extracellular K ϩ (90 mM KCl) resulted in a modest CaN-dependent NFATc4 nuclear translocation in hippocampal neurons (5,6). Stimulation of cortical neurons with NMDA induced NFATc3 and NFATc4 nuclear translocation, although the time course of translocation was not examined (21).…”

“…Ca 2ϩ influx through L-type VGCCs is especially critical for excitation-dependent gene transcription underlying important functions such as synaptic plasticity (2). Among the transcription factors activated by Ca 2ϩ influx through L-type VGCC are the nuclear factor of activated T-cells (NFAT) family of proteins, which are activated by the Ca 2ϩ /calmodulin (CaM)-dependent protein phosphatase, calcineurin (CaN) (3)(4)(5)(6). NFAT proteins were first discovered as regulators of IL-2 expression in response to antigen receptor activation in T-cells (7)(8)(9).…”

“…Here, we describe the differential regulation of the two most commonly studied NFAT isoforms in neurons, NFATc3 and NFATc4 (5,6,20,21,23,(45)(46)(47)(48)(49)(50)(51). We find that although NFATc3 is rapidly dephosphorylated and translocates to the nucleus upon depolarization, NFATc4 remains phosphorylated and localized to the cytosol.…”

L-type channel inhibition by CB1 cannabinoid receptors is mediated by PTX-sensitive G proteins and cAMP/PKA in GT1-7 hypothalamic neurons

“…As for GT1-7 cells, the inhibition of LTCCs in NTS neurons is reversible, cAMP/PKA-dependent and occurs within short times (20-30 s), suggesting rather close coupling between CB1Rs, G i,o proteins, adenylate cyclases, cAMP/PKA and LTCCs. This is somehow at variance with the slow up-regulatory effects of G protein-coupled receptors mediated by the cAMP/PKA pathway on LTCCs in myocytes [48], neuroendocrine cells [24,25,49,50], and neuronal dendrites [51] (see [52] for a review). The most likely explanation is that LTCCs modulation by cAMP/PKA is critically controlled by the co-localization of G protein-coupled receptors, Ca v 1.2 channels, adenylate cyclase and A-kinase anchoring proteins (AKAPs) (reviewed by [53]) and thus its onset and offset could vary greatly in different cell preparations.…”