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


RESULTS
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
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.
Bond
Cherie E
CE
Institute for the Future of the Mind, Department of Pharmacology, Oxford University, Oxford, UK. cherie.bond@pharm.ox.ac.uk
Zimmermann
Martina
M
Greenfield
Susan A
SA
D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D010455:Peptides / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D064569:alpha7 Nicotinic Acetylcholine Receptor
D010455:Peptides; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000110:Acetylcholinesterase