Potentiation of alpha7-containing nicotinic acetylcholine receptors by select albumins.

Neurobiology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, California 92093, USA.
Molecular Pharmacology (Impact Factor: 4.12). 03/2003; 63(2):419-28.
Source: PubMed

ABSTRACT Nicotinic receptors containing alpha7 subunits are ligand-gated ion channels widely distributed in the nervous system; they influence a diverse array of events because of their high relative calcium permeability. We show here that nicotine-induced whole-cell responses generated by such receptors can be dramatically potentiated in a rapidly reversible manner by some but not all albumins. The potentiation involves increases both in potency and efficacy with no obvious differences in rise and fall times of the response. The potentiation is not reduced by removing absorbed components; it is abolished by proteolysis, suggesting that the albumin protein backbone is essential. The fact that some albumins are ineffective indicates that minor differences in amino acid sequence may be critical. Experiments with open channel blockers indicate that the potentiation involves increased responses from active receptors rather than recruitment of receptors from a previously silent pool. Single channel recordings reveal that the potentiation correlates with increased single channel opening probability, reflected in increased frequency of channel opening and increased mean channel open time. The potentiation can be exploited to overcome blockade by noncompetitive inhibitors such as beta-amyloid peptide. The results raise the possibility that endogenous compounds use the site to modulate receptor function in vivo, and suggest that the receptors may represent useful targets for therapeutic intervention in cases where they have been implicated in neuropathologies such as Alzheimer's disease.

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    • "This may occur through increases or decreases of the impact of identified endogenous negative regulators or potentially by alterations in positive modulators. While as yet no endogenous positive modulators have been clearly identified in brain systems, the positive modulatory effects for agents such as certain serum albumins (e.g., BSA) (Conroy et al., 2003) and 5-hydrox-indole (Zwart et al., 2002) make it seem likely that such agents may exist in the brain or alternatively be developed as a new therapeutic approach for improving and maintaining cholinergic function in the aging or diseased brain. "
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