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Upregulation of alpha7 Nicotinic Receptors by Acetylcholinesterase C-Terminal Peptides.

Bond CE, Zimmermann M, Greenfield SA - PLoS ONE (2009)

Bottom Line: Of more long-term significance, these peptides also induce upregulation of alpha7-nAChR mRNA and protein expression, as well as enhancing receptor trafficking to the plasma membrane.The results reported here demonstrate a hitherto unknown relationship between the alpha7-nAChR and the non-enzymatic functions of acetylcholinesterase, mediated independently by its C-terminal domain.Such an interaction may prove valuable as a pharmacological tool, prompting new approaches for understanding, and combating, the process of neurodegeneration.

View Article: PubMed Central - PubMed

Affiliation: Institute for the Future of the Mind, Department of Pharmacology, Oxford University, Oxford, UK. cherie.bond@pharm.ox.ac.uk

ABSTRACT

Background: The alpha-7 nicotinic acetylcholine receptor (alpha7-nAChR) is well known as a potent calcium ionophore that, in the brain, has been implicated in excitotoxicity and hence in the underlying mechanisms of neurodegenerative disorders such as Alzheimer's disease. Previous research implied that the activity of this receptor may be modified by exposure to a peptide fragment derived from the C-terminal region of the enzyme acetylcholinesterase. This investigation was undertaken to determine if the functional changes observed could be attributed to peptide binding interaction with the alpha7-nAChR, or peptide modulation of receptor expression.

Methodology/principal findings: This study provides evidence that two peptides derived from the C-terminus of acetylcholinesterase, not only selectively displace specific bungarotoxin binding at the alpha7-nAChR, but also alter receptor binding properties for its familiar ligands, including the alternative endogenous agonist choline. Of more long-term significance, these peptides also induce upregulation of alpha7-nAChR mRNA and protein expression, as well as enhancing receptor trafficking to the plasma membrane.

Conclusions/significance: The results reported here demonstrate a hitherto unknown relationship between the alpha7-nAChR and the non-enzymatic functions of acetylcholinesterase, mediated independently by its C-terminal domain. Such an interaction may prove valuable as a pharmacological tool, prompting new approaches for understanding, and combating, the process of neurodegeneration.

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Representative photographs of immunofluorescent staining for α7-nAChR in GH4-hα7 cells.A. Control cells. B. Cells pretreated for 24 hr with 100 nM T14. C. Cells pretreated for 24 hr with 100 nM T30. D. Cells pretreated for 24 hr with 100 nM T15.
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pone-0004846-g007: Representative photographs of immunofluorescent staining for α7-nAChR in GH4-hα7 cells.A. Control cells. B. Cells pretreated for 24 hr with 100 nM T14. C. Cells pretreated for 24 hr with 100 nM T30. D. Cells pretreated for 24 hr with 100 nM T15.

Mentions: In addition, we examined changes in α7-nAChR protein further using immunofluorescent staining. High levels of α7-nAChR protein were detected in cellular membranes, but not in cytoplasmic or perinuclear regions (Fig. 7). Background control cells incubated with secondary antibodies, but lacking primary antibodies, did not produce a discernable signal (data not shown). After treatment for 24 hr with T14 (Fig. 7B) or T30 (Fig. 7C), enhanced signal intensity was evident in cell membranes as compared with controls (Fig. 7A), with T30-treated cells showing the greatest increase. In contrast, T15-treated cells were similar in appearance to control cells (Fig. 7D).


Upregulation of alpha7 Nicotinic Receptors by Acetylcholinesterase C-Terminal Peptides.

Bond CE, Zimmermann M, Greenfield SA - PLoS ONE (2009)

Representative photographs of immunofluorescent staining for α7-nAChR in GH4-hα7 cells.A. Control cells. B. Cells pretreated for 24 hr with 100 nM T14. C. Cells pretreated for 24 hr with 100 nM T30. D. Cells pretreated for 24 hr with 100 nM T15.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2654408&req=5

pone-0004846-g007: Representative photographs of immunofluorescent staining for α7-nAChR in GH4-hα7 cells.A. Control cells. B. Cells pretreated for 24 hr with 100 nM T14. C. Cells pretreated for 24 hr with 100 nM T30. D. Cells pretreated for 24 hr with 100 nM T15.
Mentions: In addition, we examined changes in α7-nAChR protein further using immunofluorescent staining. High levels of α7-nAChR protein were detected in cellular membranes, but not in cytoplasmic or perinuclear regions (Fig. 7). Background control cells incubated with secondary antibodies, but lacking primary antibodies, did not produce a discernable signal (data not shown). After treatment for 24 hr with T14 (Fig. 7B) or T30 (Fig. 7C), enhanced signal intensity was evident in cell membranes as compared with controls (Fig. 7A), with T30-treated cells showing the greatest increase. In contrast, T15-treated cells were similar in appearance to control cells (Fig. 7D).

Bottom Line: Of more long-term significance, these peptides also induce upregulation of alpha7-nAChR mRNA and protein expression, as well as enhancing receptor trafficking to the plasma membrane.The results reported here demonstrate a hitherto unknown relationship between the alpha7-nAChR and the non-enzymatic functions of acetylcholinesterase, mediated independently by its C-terminal domain.Such an interaction may prove valuable as a pharmacological tool, prompting new approaches for understanding, and combating, the process of neurodegeneration.

View Article: PubMed Central - PubMed

Affiliation: Institute for the Future of the Mind, Department of Pharmacology, Oxford University, Oxford, UK. cherie.bond@pharm.ox.ac.uk

ABSTRACT

Background: The alpha-7 nicotinic acetylcholine receptor (alpha7-nAChR) is well known as a potent calcium ionophore that, in the brain, has been implicated in excitotoxicity and hence in the underlying mechanisms of neurodegenerative disorders such as Alzheimer's disease. Previous research implied that the activity of this receptor may be modified by exposure to a peptide fragment derived from the C-terminal region of the enzyme acetylcholinesterase. This investigation was undertaken to determine if the functional changes observed could be attributed to peptide binding interaction with the alpha7-nAChR, or peptide modulation of receptor expression.

Methodology/principal findings: This study provides evidence that two peptides derived from the C-terminus of acetylcholinesterase, not only selectively displace specific bungarotoxin binding at the alpha7-nAChR, but also alter receptor binding properties for its familiar ligands, including the alternative endogenous agonist choline. Of more long-term significance, these peptides also induce upregulation of alpha7-nAChR mRNA and protein expression, as well as enhancing receptor trafficking to the plasma membrane.

Conclusions/significance: The results reported here demonstrate a hitherto unknown relationship between the alpha7-nAChR and the non-enzymatic functions of acetylcholinesterase, mediated independently by its C-terminal domain. Such an interaction may prove valuable as a pharmacological tool, prompting new approaches for understanding, and combating, the process of neurodegeneration.

Show MeSH
Related in: MedlinePlus