Nerve growth factor increases nicotinic ACh receptor gene expression and current density in wild-type and protein kinase A-deficient PC12 cells

Henderson, Leslie; Gdovin, Matthew J.; Liu, Chunlei; Gardner, Paul; Maue, Robert A.

doi:10.1523/jneurosci.14-03-01153.1994

Cited by 92 publications

(73 citation statements)

References 78 publications

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“…NGF-driven differentiation of PC12 cells has been extensively used as a model system to study the physiological, biochemical, and molecular mechanisms of neurotrophin signaling. In regard to neuronal nAChR, it has been demonstrated that in PC12 cells, NGF increases ACh-induced channel activity and ACh-induced macroscopic current density (4,21,48), phenomena that are thought to be a consequence of an increase in the number of functional nAChR (21). This hypothesis is consistent with observed increases in the binding of [ 3 H]nicotine (49) and of anti-nAChR antibodies (50) that occur in PC12 cells in response to NGF.…”

Section: Discussionsupporting

confidence: 60%

“…Among the neuronal genes whose expression is up-regulated in response to NGF in PC12 cells are the genes encoding several subunits (␣3, ␣5, ␣7, ␤2, and ␤4) of neuronal nicotinic acetylcholine receptors (nAChRs) (21)(22)(23). nAChRs are pentameric ligand-gated ion channels important for synaptic transmission in the nervous system (24).…”

Section: Nerve Growth Factor (Ngf)mentioning

confidence: 99%

“…nAChRs are pentameric ligand-gated ion channels important for synaptic transmission in the nervous system (24). Previously, we demonstrated that the NGF-mediated increase in nAChR gene expression is independent of cAMP-dependent protein kinase signaling (21) and that NGF treatment of PC12 cells increases the transcriptional activity of the ␤4 gene promoter (25). In this study we investigated the involvement of the other NGF-sig- naling pathways, namely MAPK, PI3-K, protein kinase C, and phospholipase C, in the regulation of nAChR gene expression.…”

Section: Nerve Growth Factor (Ngf)mentioning

confidence: 99%

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The Signal Transduction Pathway Underlying Ion Channel Gene Regulation by Sp1-c-Jun Interactions

Melnikova¹,

Gardner

2001

Journal of Biological Chemistry

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During neuronal differentiation, an exquisitely controlled program of signal transduction events takes place, leading to the temporally and spatially regulated expression of genes associated with the differentiated phenotype. A critical class of genes involved in this phenomenon is that made up of genes encoding neurotransmitter-gated ion channels that play a central role in signal generation and propagation within the nervous system. We used the well established PC12 cell line to investigate the molecular details underlying the expression of the neuronal nicotinic acetylcholine receptor class of ion channels. Neuronal differentiation of PC12 cells can be induced by nerve growth factor, leading to an increase in neuronal nicotinic acetylcholine receptor gene expression. Nerve growth factor initiates several signal transduction cascades. Here, we show that the Ras-dependent mitogen-activated protein kinase and phosphoinositide 3-kinase pathways are critical for the nerve growth factor-mediated increase in the transcriptional activity of a neuronal nicotinic acetylcholine receptor gene promoter. In addition, we show that a component of the Ras-dependent mitogen-activated protein kinase pathway, nerve growth factor-inducible c-Jun, exerts its effects on receptor gene promoter activity most likely through protein-protein interactions with Sp1. Finally, we demonstrate that the target for nerve growth factor signaling is an Sp1-binding site within the neuronal nicotinic acetylcholine receptor gene promoter.

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Section: Discussionsupporting

confidence: 60%

Section: Nerve Growth Factor (Ngf)mentioning

confidence: 99%

Section: Nerve Growth Factor (Ngf)mentioning

confidence: 99%

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The Signal Transduction Pathway Underlying Ion Channel Gene Regulation by Sp1-c-Jun Interactions

Melnikova¹,

Gardner

2001

Journal of Biological Chemistry

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“…S4). In these experiments, we used neuronally differentiated PC12 cells that predominantly express a3b4 nAChR subtype (Avila et al, 2003;Henderson et al, 1994) and gave larger and more reproducible amperometric responses to ACh as found by us and other investigators (Nery et al, 2010) compared with un-differentiated PC12 cells.…”

Section: Effect Of Human Cst Variants On Blockade Of Acetylcholine-evmentioning

confidence: 89%

Molecular mechanism of interactions of the physiological anti-hypertensive peptide catestatin with the neuronal nicotinic acetylcholine receptor

Sahu

Mohan

Sahu

et al. 2012

Journal of Cell Science

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SummaryCatestatin (CST), a chromogranin-A-derived peptide, is a potent endogenous inhibitor of the neuronal nicotinic acetylcholine receptor (nAChR). It exerts an anti-hypertensive effect by acting as a 'physiological brake' on transmitter release into the circulation. However, the mechanism of interaction of CST with nAChR is only partially understood. To unravel molecular interactions of the wild-type human CST (CST-WT) as well as its naturally occurring variants (CST-364S and CST-370L, which have GlyRSer and ProRLeu substitutions, respectively) with the human a3b4 nAChR, we generated a homology-modeled human a3b4 nAChR structure and solution structures of CST peptides. Docking and molecular dynamics simulations showed that ,90% of interacting residues were within 15 N-terminal residues of CST peptides. The rank order of binding affinity of these peptides with nAChR was: CST-370L.CST-WT.CST-364S; the extent of occlusion of the receptor pore by these peptides was also in the same order. In corroboration with computational predictions, circular dichroism analysis revealed significant differences in global structures of CST peptides (e.g. the order of a-helical content was: CST-370L.CST-WT.CST-364S). Consistently, CST peptides blocked various stages of nAChR signal transduction, such as nicotine-or acetylcholine-evoked inward current, rise in intracellular Ca 2+ and catecholamine secretion in or from neuron-differentiated PC12 cells, in the same rank order. Taken together, this study shows molecular interactions between human CST peptides and human a3b4 nAChR, and demonstrates that alterations in the CST secondary structure lead to the gain of potency for CST-370L and loss of potency for CST-364S. These findings have implications for understanding the nicotinic cholinergic signaling in humans.

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“…It is important to determine if this effect extends to nAChR protein expression given the functional implications of such regulation. To address this critical issue, we used the rat pheochromocytoma cell line, PC12, which expresses relatively high levels of nAChR subunits following nerve growth factor treatment (Henderson et al 1994). PC12 cells were transfected with either miR-542-3p mimic or inhibitor followed by 3 d of nerve growth factor treatment and subsequent immunoblotting.…”

Section: Mirna Regulation Of Endogenous Nachr Expressionmentioning

confidence: 99%

miRNAome analysis of the mammalian neuronal nicotinic acetylcholine receptor gene family

Hogan

Casserly

Scofield

et al. 2014

RNA

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Nicotine binds to and activates a family of ligand-gated ion channels, neuronal nicotinic acetylcholine receptors (nAChRs). Chronic nicotine exposure alters the expression of various nAChR subtypes, which likely contributes to nicotine dependence; however, the underlying mechanisms regulating these changes remain unclear. A growing body of evidence indicates that microRNAs (miRNAs) may be involved in nAChR regulation. Using bioinformatics, miRNA library screening, site-directed mutagenesis, and gene expression analysis, we have identified a limited number of miRNAs that functionally interact with the 3 ′ -untranslated regions (3 ′ UTRs) of mammalian neuronal nAChR subunit genes. In silico analyses revealed specific, evolutionarily conserved sites within the 3 ′ UTRs through which the miRNAs regulate gene expression. Mutating these sites disrupted miRNA regulation confirming the in silico predictions. In addition, the miRNAs that target nAChR 3 ′ UTRs are expressed in mouse brain and are regulated by chronic nicotine exposure. Furthermore, we show that expression of one of these miRNAs, miR-542-3p, is modulated by nicotine within the mesocorticolimbic reward pathway. Importantly, overexpression of miR-542-3p led to a decrease in the protein levels of its target, the nAChR β2 subunit. Bioinformatic analysis suggests that a number of the miRNAs play a general role in regulating cholinergic signaling. Our results provide evidence for a novel mode of nicotine-mediated regulation of the mammalian nAChR gene family.

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Nerve growth factor increases nicotinic ACh receptor gene expression and current density in wild-type and protein kinase A-deficient PC12 cells

Cited by 92 publications

References 78 publications

The Signal Transduction Pathway Underlying Ion Channel Gene Regulation by Sp1-c-Jun Interactions

The Signal Transduction Pathway Underlying Ion Channel Gene Regulation by Sp1-c-Jun Interactions

Molecular mechanism of interactions of the physiological anti-hypertensive peptide catestatin with the neuronal nicotinic acetylcholine receptor

miRNAome analysis of the mammalian neuronal nicotinic acetylcholine receptor gene family

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