Calcium channel activation stabilizes a neuronal calcium channel mRNA

Schorge, Stephanie; Gupta, Shivali; Lin, Zhixin; McEnery, Maureen W.; Lipscombe, Diane

doi:10.1038/12153

Cited by 26 publications

(16 citation statements)

References 50 publications

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“…Similar activity-dependent downregulation of Na ϩ channels occurs in skeletal and cardiac muscle cells (77,105,452,538), where there is direct evidence that the effects are secondary to Ca 2ϩ entry. Activity has been reported to upregulate Na ϩ channel density in a Ca 2ϩ -dependent manner in GH3 cells (417 (528). In DRG neurons, Ca 2ϩ currents show similar dependence on the specific patterns of stimulation as do other activity-regulated molecules (331).…”

Section: ؉ -Gated Channelsmentioning

confidence: 81%

Ion Channel Development, Spontaneous Activity, and Activity-Dependent Development in Nerve and Muscle Cells

Moody¹,

Bosma²

2005

Physiological Reviews

340

323

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At specific stages of development, nerve and muscle cells generate spontaneous electrical activity that is required for normal maturation of intrinsic excitability and synaptic connectivity. The patterns of this spontaneous activity are not simply immature versions of the mature activity, but rather are highly specialized to initiate and control many aspects of neuronal development. The configuration of voltage- and ligand-gated ion channels that are expressed early in development regulate the timing and waveform of this activity. They also regulate Ca2+ influx during spontaneous activity, which is the first step in triggering activity-dependent developmental programs. For these reasons, the properties of voltage- and ligand-gated ion channels expressed by developing neurons and muscle cells often differ markedly from those of adult cells. When viewed from this perspective, the reasons for complex patterns of ion channel emergence and regression during development become much clearer.

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Section: ؉ -Gated Channelsmentioning

confidence: 81%

Ion Channel Development, Spontaneous Activity, and Activity-Dependent Development in Nerve and Muscle Cells

Moody¹,

Bosma²

2005

Physiological Reviews

340

323

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“…For example, depolarization stabilizes mRNA for an N-type calcium channel subunit in cultured SCG neurons (24). To get an idea of the relative contribution of transcription versus mRNA stability, we blocked transcription pharmacologically with actinomycin D. We infected sympathetic neurons overnight with the hCMV-GFP construct, and 1 day later we treated them with high K ϩ or left them in control medium.…”

Section: Resultsmentioning

confidence: 99%

Depolarization Strongly Induces Human Cytomegalovirus Major Immediate-Early Promoter/Enhancer Activity in Neurons

Wheeler

Cooper

2001

Journal of Biological Chemistry

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Activity-dependent changes in gene expression involving the transcription factor cAMP-response element-binding protein (CREB) occur in learning and memory, pain, and drug addiction. This mechanism may also be important for cytomegaloviral infections of the brain. The human cytomegalovirus major immediateearly promoter/enhancer (hCMV promoter), rate-limiting for productive cytomegalovirus infection, contains five cAMP-response elements (CREs). Indirect evidence suggests that this promoter does not function in unstimulated neurons. Here we test the hypothesis that expression from the hCMV promoter in neurons is induced by membrane depolarization. For these experiments, we infected cultured sympathetic and hippocampal neurons with hCMV-green fluorescent protein (GFP) promoter/reporter constructs using adenoviral gene transfer techniques and measured transgene expression by quantifying GFP fluorescence and GFP mRNA levels. We found that depolarization up-regulates promoter activity by >90-fold. Moreover, our results from pharmacological experiments suggest that this induction occurred through a CREB-dependent pathway. Importantly, site-directed mutagenesis of all five CREs in the promoter blocked this up-regulation almost completely, whereas mutating four of them had no effect. We conclude that the hCMV promoter acts as a molecular switch in neurons and is strongly induced by membrane depolarization, neuronal activity, or other stimuli that activate CREB. These results may provide insight into molecular mechanisms of cytomegalovirus-related diseases of the brain. Human cytomegalovirus (hCMV)1 infections, often harmless in healthy individuals, produce numerous debilitating symptoms in those with immature or impaired immune systems. In persons with AIDS, for example, cytomegalovirus infections cause severe neurological disorders (1); in infants, congenital infections cause impaired brain growth, mental retardation, and progressive motor deficits (2). Therefore, it is important to understand the mechanisms for cytomegalovirus production in the nervous system. Productive cytomegaloviral infections require transcription of immediate-early genes in the viral genome (3, 4). Expression of these genes is controlled by the hCMV major immediate-early promoter/enhancer (hCMV promoter) (5). As activity of this promoter is rate-limiting for productive viral infection, many groups have studied how this promoter functions to understand the molecular mechanisms of cytomegalovirus infections. The hCMV promoter is highly enriched with a densely packed array of cis-elements (3) and is among the strongest known promoters in mammalian cells. As such, it is commonly used to drive the expression of foreign genes in a wide variety of cell types. Surprisingly, the hCMV promoter appears not to function well in neurons. For example, studies using primary cortical cultures indicate that the hCMV promoter expresses transgenes well in glia but not in neurons (6). Furthermore, in mice transgenic for hCMV promoter-reporter constructs, only a few ne...

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“…To examine whether there might therefore be a secondary effect on Ca V 2.2 mRNA levels of interaction between the fulllength and the truncated Ca V 2.2 proteins, we coexpressed Ca V 2.2-Dom I with full-length Ca V 2.2 and accessory subunits and examined mRNA levels in individual Xenopus oocytes injected with cDNA. Because the stability of Ca V 2.2 mRNA has also been shown to be governed by sequences in the 3Ј UTR (Schorge et al, 1999), in the present study the 3Ј UTR was removed from the Ca V 2.2 construct used for the oocyte expression experiments. In all these oocytes, I Ba was measured to ensure expression.…”

Section: Does the Suppression Of Ca V Expression By Truncated Construmentioning

confidence: 99%

Dominant-Negative Calcium Channel Suppression by Truncated Constructs Involves a Kinase Implicated in the Unfolded Protein Response

Page

Heblich²,

Davies³

et al. 2004

Journal of Neuroscience

101

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Expression of the calcium channel Ca V 2.2 is markedly suppressed by coexpression with truncated constructs of Ca V 2.2. Furthermore, a two-domain construct of Ca V 2.1 mimicking an episodic ataxia-2 mutation strongly inhibited Ca V 2.1 currents. We have now determined the specificity of this effect, identified a potential mechanism, and have shown that such constructs also inhibit endogenous calcium currents when transfected into neuronal cell lines. Suppression of calcium channel expression requires interaction between truncated and full-length channels, because there is inter-subfamily specificity. Although there is marked cross-suppression within the Ca V 2 calcium channel family, there is no cross-suppression between Ca V 2 and Ca V 3 channels. The mechanism involves activation of a component of the unfolded protein response, the endoplasmic reticulum resident RNA-dependent kinase (PERK), because it is inhibited by expression of dominant-negative constructs of this kinase. Activation of PERK has been shown previously to cause translational arrest, which has the potential to result in a generalized effect on protein synthesis. In agreement with this, coexpression of the truncated domain I of Ca V 2.2, together with full-length Ca V 2.2, reduced the level not only of Ca V 2.2 protein but also the coexpressed ␣2␦-2. Thapsigargin, which globally activates the unfolded protein response, very markedly suppressed Ca V 2.2 currents and also reduced the expression level of both Ca V 2.2 and ␣2␦-2 protein. We propose that voltage-gated calcium channels represent a class of difficult-to-fold transmembrane proteins, in this case misfolding is induced by interaction with a truncated cognate Ca V channel. This may represent a mechanism of pathology in episodic ataxia-2.

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Calcium channel activation stabilizes a neuronal calcium channel mRNA

Cited by 26 publications

References 50 publications

Ion Channel Development, Spontaneous Activity, and Activity-Dependent Development in Nerve and Muscle Cells

Ion Channel Development, Spontaneous Activity, and Activity-Dependent Development in Nerve and Muscle Cells

Depolarization Strongly Induces Human Cytomegalovirus Major Immediate-Early Promoter/Enhancer Activity in Neurons

Dominant-Negative Calcium Channel Suppression by Truncated Constructs Involves a Kinase Implicated in the Unfolded Protein Response

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