Upregulation of α7 Nicotinic Receptors by Acetylcholinesterase C-Terminal Peptides

Abstract

BackgroundThe alpha-7 nicotinic acetylcholine receptor (α7-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 α7-nAChR, or peptide modulation of receptor expression.Methodology/Principal FindingsThis study provides evidence that two peptides derived from the C-terminus of acetylcholinesterase, not only selectively displace specific bungarotoxin binding at the α7-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 α7-nAChR mRNA and protein expression, as well as enhancing receptor trafficking to the plasma membrane.Conclusions/SignificanceThe results reported here demonstrate a hitherto unknown relationship between the α7-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.

Neuronal AChE splice variants and their non‐hydrolytic functions: redefining a target of AChE inhibitors?

“…The resulting, AChE‐Tt remains enzymatically active (, Zimmermann et al ., ). T30, in turn, manipulates α7‐nAChR expression (, Bond et al ., ), and trophic‐toxic actions are triggered by means of Ca 2+ influx (), depending on the T30 dose (Greenfield et al ., ). AChE‐Tt activity is further enhanced by T30 (; Zimmermann et al ., ), on which breakdown of α7‐nAChR‐stimulating ACh is contingent ().…”

“…As regards degenerative processes, the role of both AChE -specifically AChE-T -and the α7-nAChR have been widely discussed (Sternfeld et al, 2000;O'Neill et al, 2002;Jin et al, 2004;Rees et al, 2005;Holzgrabe et al, 2007;Schliebs and Arendt, 2011). Recent work now conclusively reveals that the two AChE C-terminal peptides T14 and, particularly, T30 are involved in binding interactions with the α7-nAChR, modulating its mRNA as well as protein expression (Bond et al, 2009).…”

Smoking, nicotine and neuropsychiatric disorders

“…These peptides bind to a7 nAChRs and alter the affinity of a7 nAChRs to their natural ligands and also upregulate a7 nAChRs. All the interactions mentioned above, however, are too complex to be discussed in detail here (Lane et al, 2006;Oddo and LaFerla, 2006;Liu and Wu, 2006;Dineley, 2007;Small et al, 2007;Kadir et al, 2008;Kadir et al, 2007;Nordberg, 2006a,b;Colciaghi et al, 2004;Inestrosa et al, 2008;Fisher, 2007;Bond et al, 2009;Greenfield et al, 2004;Perry et al, 2004).…”

Positive and negative modulation of nicotinic receptors

“…Although initially a 14 amino acid peptide derived from the C-terminus of acetylcholinesterase (i.e., AEFHRWSSYMVHWK) was found to behave as a PAM Zbarsky et al, 2004), new evidence indicates that this peptide and another of 30 amino acids partially inhibit [ 125 I]a-BTx binding in living cells with two different components, suggesting that they interact with two binding sites of different affinities, whereas they decrease choline affinity when cell membranes were used instead (Bond et al, 2009). Chronic incubation with these peptides increases the number of a7 AChRs in a methyllycaconitine-specific manner and decreases [ 125 I]a-BTx affinity.…”