A novel peptide modulates α7 nicotinic receptor responses: implications for a possible trophic‐toxic mechanism within the brain

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Abstract
The α7 nicotinic acetylcholine receptor (nAChR) plays a key role in neural development and neurodegeneration. Here, we identify a novel, modulatory receptor ligand, a 14‐amino acid peptide (AEFHRWSSYMVHWK) derived from the C‐terminus of acetylcholinesterase (AChE). In three different in vitro preparations, this ‘AChE‐peptide’ is bioactive in a ligand‐specific and concentration‐dependent manner. First, it modulates acutely the effect of acetylcholine (ACh) on Xenopus oocytes transfected with human α7, but not α4/β2, nAChR. The action persists when intracellular calcium is chelated with BAPTA or when calcium is substituted with barium ions. This observation suggests that intracellular Ca2+ signals do not mediate the interaction between the peptide and nAChR, but rather that the interaction is direct: however, the intervention of other mediators cannot be excluded. Secondly, in recordings from the CA1 region in guinea‐pig hippocampal slices, AChE‐peptide modulates synaptic plasticity in a α‐bungarotoxin (α‐BgTx)‐sensitive manner. Thirdly, in organotypic cultures of rat hippocampus, long‐term exposure to peptide attenuates neurite outgrowth: this chronic, functional effect is selectively blocked by the α7 nAChR antagonists, α‐BgTx and methyllycaconitine, but not by the α4/β2‐preferring blocker dihydro‐β‐ethroidine. A scrambled peptide variant, and the analogous peptide from butyrylcholinesterase, are ineffective in all three paradigms. The consequences of this novel modulation of the α7 nAChR may be activation of a trophic‐toxic axis, of relevance to neurodegeneration.