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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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Specific saturation binding on cell membranes after chronic treatment of GH4-hα7 cells with 100 nM T-AChE peptides for 24 hr.Data shown are the average±SEM of 2 separate experiments each performed in triplicate.
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pone-0004846-g004: Specific saturation binding on cell membranes after chronic treatment of GH4-hα7 cells with 100 nM T-AChE peptides for 24 hr.Data shown are the average±SEM of 2 separate experiments each performed in triplicate.

Mentions: We next examined the effects of chronic peptide exposure on the number of α7-nAChR receptor binding sites and receptor affinity for [125I]α-BTX binding (Fig. 4). Cells in culture were exposed to AChE peptides for 24 hr, then saturation binding assays were performed on purified cell membranes using [125I]α-BTX in concentrations ranging from 0.033 to 33.0 nM. After 24 hr treatment with T14 or T30, a significant increase (p = 0.0004 and p<0.0001 respectively) in the number of α7-nAChR binding sites, as determined by maximal binding values, was observed (Fig. 4). Additionally, the affinity of receptors for [125I]α-BTX was significantly decreased (T14, p = 0.0035; T30, p = 0.0018) as compared with controls. In contrast to that seen for T14 and T30 peptides, T15 treatment for 24 hr had no effect on specific binding affinity of [125I]α-BTX to the α7-nAChR or on the number of available receptor binding sites (Fig. 4). Average Bmax and Kd values for α7-nAChR binding after chronic peptide exposure are summarized in Table 2.


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

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

Specific saturation binding on cell membranes after chronic treatment of GH4-hα7 cells with 100 nM T-AChE peptides for 24 hr.Data shown are the average±SEM of 2 separate experiments each performed in triplicate.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0004846-g004: Specific saturation binding on cell membranes after chronic treatment of GH4-hα7 cells with 100 nM T-AChE peptides for 24 hr.Data shown are the average±SEM of 2 separate experiments each performed in triplicate.
Mentions: We next examined the effects of chronic peptide exposure on the number of α7-nAChR receptor binding sites and receptor affinity for [125I]α-BTX binding (Fig. 4). Cells in culture were exposed to AChE peptides for 24 hr, then saturation binding assays were performed on purified cell membranes using [125I]α-BTX in concentrations ranging from 0.033 to 33.0 nM. After 24 hr treatment with T14 or T30, a significant increase (p = 0.0004 and p<0.0001 respectively) in the number of α7-nAChR binding sites, as determined by maximal binding values, was observed (Fig. 4). Additionally, the affinity of receptors for [125I]α-BTX was significantly decreased (T14, p = 0.0035; T30, p = 0.0018) as compared with controls. In contrast to that seen for T14 and T30 peptides, T15 treatment for 24 hr had no effect on specific binding affinity of [125I]α-BTX to the α7-nAChR or on the number of available receptor binding sites (Fig. 4). Average Bmax and Kd values for α7-nAChR binding after chronic peptide exposure are summarized in Table 2.

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