Title

Chaperone Protein 14-3-3 And Protein Kinase A Increase The Relative Abundance Of Low Agonist Sensitivity Human α4β2 Nicotinic Acetylcholine Receptors In Xenopus Oocytes

Department

neurobiology

Document Type

Article

Abstract

α4 and β2 nicotinic acetylcholine (nACh) receptor subunits expressed heterologously in Xenopus oocytes assemble into a mixture of receptors with high and low agonist sensitivity whose relative abundance is influenced by the heteropentamer subunit ratio. We have found that inhibition of protein kinase A by KT5720 decreased maximal [3H]cytisine binding and acetylcholine (ACh)-induced current responses, and increased the relative proportion of α4β2 receptors with high agonist sensitivity. Mutation of serine 467, a putative protein kinase A substrate in a chaperone protein binding motif within the large cytoplasmic domain of the α4 subunit, to alanine or asparate decreased or increased, respectively, maximal [ 3H]cytisine binding and ACh response amplitude. Expression of α4S467A mutant subunits decreased steady levels of α4 and the relative proportion of α4β2 receptors with low agonist sensitivity, whilst expression of α4S467D increased steady levels of α4 and α4β2 receptors with low agonist sensitivity. Difopein, an inhibitor of chaperone 14-3-3 proteins, decreased [3H]cytisine binding and ACh responses and increased the proportion of α4β2 with high sensitivity to activation by ACh. Thus, post-translational modification affecting steady-state levels of α4 subunits provides a possible means for physiologically relevant, chaperone-mediated variation in the relative proportion of high and low agonist sensitivity α4β2 nACh receptors. © 2006 The Authors.

Publication Date

8-1-2006

Publication Title

Journal of Neurochemistry

ISSN

00223042

Volume

98

Issue

3

First Page

876

Last Page

885

Digital Object Identifier (DOI)

10.1111/j.1471-4159.2006.03915.x

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