Upregulation of L-Type Ca<sup>2+</sup>Channels in Reactive Astrocytes after Brain Injury, Hypomyelination, and Ischemia

Westenbroek, Ruth E.; Bausch, Suzanne B.; Lin, R.C.S.; Franck, J. E.; Noebels, Jeffery L.; Catterall, William A.

doi:10.1523/jneurosci.18-07-02321.1998

Cited by 136 publications

(74 citation statements)

References 90 publications

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“…One possible source of Ca 2ϩ dysregulation is the increased L-type Ca 2ϩ channel activity that develops in hippocampal neurons with aging (Thibault and Landfield, 1996). This potential mechanism seems of particular interest in this context, because a similar upregulation of L-type channels occurs in astrocytes in regions of injury/ischemia (Westenbroek et al, 1998). In astrocytes, however, the increased L-type channel activity may provide signals for upregulation of calcineurin expression as well as activity.…”

Section: Discussionmentioning

confidence: 99%

Calcineurin Triggers Reactive/Inflammatory Processes in Astrocytes and Is Upregulated in Aging and Alzheimer's Models

Norris

Kadish²,

Blalock³

et al. 2005

J. Neurosci.

202

210

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Astrocyte reactivity (i.e., activation) and associated neuroinflammation are increasingly thought to contribute to neurodegenerative disease. However, the mechanisms that trigger astrocyte activation are poorly understood. Here, we studied the Ca 2ϩ -dependent phosphatase calcineurin, which regulates inflammatory signaling pathways in immune cells, for a role in astrogliosis and brain neuroinflammation. Adenoviral transfer of activated calcineurin to primary rat hippocampal cultures resulted in pronounced thickening of astrocyte somata and processes compared with uninfected or virus control cultures, closely mimicking the activated hypertrophic phenotype. This effect was blocked by the calcineurin inhibitor cyclosporin A. Parallel microarray studies, validated by extensive statistical analyses, showed that calcineurin overexpression also induced genes and cellular pathways representing most major markers associated with astrocyte activation and recapitulated numerous changes in gene expression found previously in the hippocampus of normally aging rats or in Alzheimer's disease (AD). No genomic or morphologic evidence of apoptosis or damage to neurons was seen, indicating that the calcineurin effect was mediated by direct actions on astrocytes. Moreover, immunocytochemical studies of the hippocampus/neocortex in normal aging and AD model mice revealed intense calcineurin immunostaining that was highly selective for activated astrocytes. Together, these studies show that calcineurin overexpression is sufficient to trigger essentially the full genomic and phenotypic profiles associated with astrocyte activation and that hypertrophic astrocytes in aging and AD models exhibit dramatic upregulation of calcineurin. Thus, the data identify calcineurin upregulation in astrocytes as a novel candidate for an intracellular trigger of astrogliosis, particularly in aging and AD brain.

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Section: Discussionmentioning

confidence: 99%

Calcineurin Triggers Reactive/Inflammatory Processes in Astrocytes and Is Upregulated in Aging and Alzheimer's Models

Norris

Kadish²,

Blalock³

et al. 2005

J. Neurosci.

202

210

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“…The blockade of VOCC in the latter conditions is associated with a reduction of fibrosis. 37,38 The potential mechanisms regulating the expression of VOCC during the activation of HSCs were not analyzed in this study and remain speculative. In other cell types, stimulation of cells with growth factors increases the expression of VOCC.…”

Section: Discussionmentioning

confidence: 99%

In vitro and in vivo activation of rat hepatic stellate cells results in de novo expression of L-type voltage-operated calcium channels

et al. 2001

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Following chronic liver injury, hepatic stellate cells (HSCs) transdifferentiate into myofibroblast-like cells, which develop contractile properties and contribute to increased resistance to blood flow. We investigated whether this phenotypic activation includes changes in the expression of L-type voltage-operated Ca 2؉ channels (VOCC), which mediate Ca 2؉ influx and regulate cell contraction in vascular cell types. Rat HSCs were studied in the quiescent phenotype and after their activation in vitro (cultured on plastic for 14 days) and in vivo (isolated from rats with CCl 4 -induced cirrhosis). Patch-clamp studies showed Ca 2؉ currents through L-type VOCC in HSCs activated both in vitro and in vivo, whereas no currents were detected in quiescent HSCs. Moreover, binding studies with 3 H-isradipine, a specific L-type VOCC antagonist, showed a large number of binding sites in activated HSCs, while no specific binding was found in quiescent HSCs. In chronic liver diseases, hepatic stellate cells (HSCs) transdifferentiate from a quiescent phenotype into a myofibroblastlike phenotype, a process also named "activation." 1,2 The most relevant consequence of this phenotypic activation is the increased secretion of components of the extracellular matrix, a key feature in liver fibrogenesis. 3 In addition, recent data indicate that another important consequence of this process is the acquisition of contractile properties. 4 Due to their strategic anatomical location around hepatic sinusoids, tonic contraction of activated HSCs in response to agonists may increase sinusoidal resistance to blood flow and thus play an important role in the pathogenesis of portal hypertension in advanced chronic liver diseases. 5,6 In the last decade, much attention has been focused on the molecular mechanisms responsible for the increased collagen synthesis that display HSCs following phenotypic activation. 7 In clear contrast with these advances, the mechanisms by which the phenotypic activation of HSCs results in increased cell contractility remain largely unknown. Studies using in vitro and in vivo models of HSC activation have constantly shown that activated HSCs express high amounts of ␣-smooth muscle actin and myosin, cytosolic proteins essential for cell contractility, which are absent in quiescent HSCs. 8,9 Moreover, recent data indicate that in vitro activation of HSCs results in increased sensitivity to vasoconstrictor and depolarizing substances when assessed in terms of Ca 2ϩ mobilization. 10,11 However, the mechanisms underlying this increased Ca 2ϩ response are unknown. In human activated HSCs, an agonist-induced increase in intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) is largely mediated by the opening of L-type voltage-operated Ca 2ϩ channels (VOCC), 12,13 which are known to regulate Ca 2ϩ entry and thereby cell contraction in other vascular cell types. 14 We hypothesized that the process of activation of HSCs is associated with changes in the expression of L-type VOCC that mediate Ca 2ϩ mobilization and cell contraction. ...

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“…Control experiments were performed to confirm the specificity of labeling by omitting the primary antibody and using peptideblocked antibodies as described previously (30,35). Double labeling using two rabbit polyclonal antibodies was carried out as described (36).…”

Section: Methodsmentioning

confidence: 99%

Functional Roles of a C-terminal Signaling Complex of CaV1 Channels and A-kinase Anchoring Protein 15 in Brain Neurons

Marshall

Clark

Westenbroek

et al. 2011

Journal of Biological Chemistry

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Regulation of Ca V 1.2 channels in cardiac myocytes by the ␤-adrenergic pathway requires a signaling complex in which the proteolytically processed distal C-terminal domain acts as an autoinhibitor of channel activity and mediates up-regulation by the ␤-adrenergic receptor and PKA bound to A-kinase anchoring protein 15 (AKAP15). We examined the significance of this distal C-terminal signaling complex for Ca V 1.2 and Ca V 1.3 channels in neurons. AKAP15 co-immunoprecipitates with Ca V 1.2 and Ca V 1.3 channels. AKAP15 has overlapping localization with Ca V 1.2 and Ca V 1.3 channels in cell bodies and proximal dendrites and is closely co-localized with Ca V 1.2 channels in punctate clusters. The neuronal AKAP MAP2B, which also interacts with Ca V 1.2 and Ca V 1.3 channels, has complementary localization to AKAP15, suggesting different functional roles in calcium channel regulation. Studies with mice that lack the distal C-terminal domain of Ca V 1.2 channels (Ca V 1.2⌬DCT) reveal that AKAP15 interacts with neuronal Ca V 1.2 channels via their C terminus in vivo and is co-localized in punctate clusters of Ca V 1.2 channels via that interaction. Ca V 1.2⌬DCT neurons have reduced L-type calcium current, indicating that the distal C-terminal domain is required for normal functional expression in vivo. Deletion of the distal C-terminal domain impairs calcium-dependent signaling from Ca V 1.2 channels to the nucleus, as shown by reduction in phosphorylation of the cAMP response element-binding protein. Our results define AKAP signaling complexes of Ca V 1.2 and Ca V 1.3 channels in brain and reveal three previously unrecognized functional roles for the distal C terminus of neuronal Ca V 1.2 channels in vivo: increased functional expression, anchoring of AKAP15 and PKA, and initiation of excitation-transcription coupling.Voltage-gated calcium channels of the Ca V 1 subfamily conduct L-type calcium currents that transduce cell-surface depolarization into calcium transients and initiate excitation-contraction coupling, excitation-secretion coupling, protein phosphorylation, and gene regulation (1-5). Calcium influx via postsynaptic Ca V 1 channels supports sustained phosphorylation of cAMP response element-binding protein (CREB) 3 and CREB-dependent gene expression in hippocampal neurons (6 -13).Functional Ca V 1 channels are multimeric complexes composed of pore-forming ␣ 1 and associated ␣ 2 ␦, ␤, and in some cases, ␥ subunits (14 -19). These channels have an extended C terminus containing many protein interaction sites for regulation (5). In brain, Ca V 1 channels are composed of 70% Ca V 1.2 and 22% Ca V 1.3 with minor contributions from other Ca V 1 channels, as indicated by immunoprecipitation with specific antibodies (20). Ca V 1.2 and Ca V 1.3 channels are primarily localized in the soma and proximal dendrites (20, 21).The ␤-adrenergic pathway activates cAMP-dependent protein kinase (PKA) and increases the activity of Ca V 1 channels in skeletal and cardiac myocytes and neurons (1-5, 22, 23). PKAmediated regulatio...

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Upregulation of L-Type Ca²⁺Channels in Reactive Astrocytes after Brain Injury, Hypomyelination, and Ischemia

Cited by 136 publications

References 90 publications

Calcineurin Triggers Reactive/Inflammatory Processes in Astrocytes and Is Upregulated in Aging and Alzheimer's Models

Calcineurin Triggers Reactive/Inflammatory Processes in Astrocytes and Is Upregulated in Aging and Alzheimer's Models

In vitro and in vivo activation of rat hepatic stellate cells results in de novo expression of L-type voltage-operated calcium channels

Functional Roles of a C-terminal Signaling Complex of CaV1 Channels and A-kinase Anchoring Protein 15 in Brain Neurons

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Upregulation of L-Type Ca2+Channels in Reactive Astrocytes after Brain Injury, Hypomyelination, and Ischemia

Cited by 136 publications

References 90 publications

Calcineurin Triggers Reactive/Inflammatory Processes in Astrocytes and Is Upregulated in Aging and Alzheimer's Models

Calcineurin Triggers Reactive/Inflammatory Processes in Astrocytes and Is Upregulated in Aging and Alzheimer's Models

In vitro and in vivo activation of rat hepatic stellate cells results in de novo expression of L-type voltage-operated calcium channels

Functional Roles of a C-terminal Signaling Complex of CaV1 Channels and A-kinase Anchoring Protein 15 in Brain Neurons

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Product

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Upregulation of L-Type Ca²⁺Channels in Reactive Astrocytes after Brain Injury, Hypomyelination, and Ischemia