Molecular Modulation of Human ?7 Nicotinic Receptor by Amyloid-? Peptides.

ABSTRACT: Amyloid ? peptide (A?) is a key player in the development of Alzheimer's disease (AD). It is the primary component of senile plaques in AD patients and is also found in soluble forms. Cholinergic activity mediated by ?7 nicotinic receptors has been shown to be affected by A? soluble forms. To shed light into the molecular mechanism of this effect, we explored the direct actions of oligomeric A?1-40 and A?1-42 on human ?7 by fluorescence spectroscopy and single-channel recordings. Fluorescence measurements using the conformational sensitive probe crystal violet (CrV) revealed that in the presence of A? ?7 undergoes concentration-dependent conformational changes. Exposure of ?7 to 100 pM A? changes CrV KD towards that of the desensitized state. However, ?7 is still reactive to high carbamylcholine (Carb) concentrations. These observations are compatible with the induction of active/desensitized states as well as of a novel conformational state in the presence of both A? and Carb. At 100 nM A?, ?7 adopts a resting-state-like structure which does not respond to Carb, suggesting stabilization of ?7 in a blocked state. In real time, we found that A? is capable of eliciting ?7 channel activity either in the absence or presence of the positive allosteric modulator (PAM) PNU-120596. Activation by A? is favored at picomolar or low nanomolar concentrations and is not detected at micromolar concentrations. At high A? concentrations, the mean duration of activation episodes elicited by ACh in the presence of PNU-120596 is significantly reduced, an effect compatible with slow open-channel block. We conclude that A? directly affects ?7 function by acting as an agonist and a negative modulator. Whereas the capability of low concentrations of A? to activate ?7 could be beneficial, the reduced ?7 activity in the presence of higher A? concentrations or its long exposure may contribute to the cholinergic signaling deficit and may be involved in the initiation and development of AD.

SUBMITTER: Lasala M 

PROVIDER: S-EPMC6376857 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature