alpha-conotoxins PnIA and [A10L] PnIA stabilize different states of the alpha 7-L247T nicotinic acetylcholine receptor

Hogg, R. C., Hopping, G., Alewood, P. F., Adams, D. J. and Bertrand, D. (2003) alpha-conotoxins PnIA and [A10L] PnIA stabilize different states of the alpha 7-L247T nicotinic acetylcholine receptor. Journal of Biological Chemistry, 278 29: 26908-26914. doi:10.1074/jbc.M212628200

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Author Hogg, R. C.
Hopping, G.
Alewood, P. F.
Adams, D. J.
Bertrand, D.
Title alpha-conotoxins PnIA and [A10L] PnIA stabilize different states of the alpha 7-L247T nicotinic acetylcholine receptor
Formatted title
α-conotoxins PnIA and [A10L]PnIA stabilize different states of the α7-L247T nicotinic acetylcholine receptor
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
Publication date 2003-07-18
Sub-type Article (original research)
DOI 10.1074/jbc.M212628200
Open Access Status File (Publisher version)
Volume 278
Issue 29
Start page 26908
End page 26914
Total pages 7
Editor Herbert Tabor
Place of publication Bethesda, USA
Publisher American Society for Biochemistry and Molecular Biology, Inc.
Collection year 2003
Language eng
Subject C1
270100 Biochemistry and Cell Biology
780103 Chemical sciences
320502 Basic Pharmacology
250302 Biological and Medical Chemistry
730104 Nervous system and disorders
780105 Biological sciences
Abstract The effects of the native alpha-conotoxin PnIA, its synthetic derivative [ A10L] PnIA and alanine scan derivatives of [ A10L] PnIA were investigated on chick wild type alpha7 and alpha7-L247T mutant nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus oocytes. PnIA and [A10L] PnIA inhibited acetylcholine (ACh)-activated currents at wtalpha7 receptors with IC50 values of 349 and 168 nM, respectively. Rates of onset of inhibition were similar for PnIA and [ A10L] PnIA; however, the rate of recovery was slower for [ A10L] PnIA, indicating that the increased potency of [ A10L] PnIA at alpha7 receptors is conveyed by its slower rate of dissociation from the receptors. All the alanine mutants of [ A10L] PnIA inhibited ACh-activated currents at wtalpha7 receptors. Insertion of an alanine residue between position 5 and 13 and at position 15 significantly reduced the ability of [ A10L] PnIA to inhibit ACh-evoked currents. PnIA inhibited the non-desensitizing ACh-activated currents at alpha7-L247T receptors with an IC50 194 nM. In contrast, [ A10L] PnIA and the alanine mutants potentiated the ACh-activated current alpha7-L247T receptors and in addition [ A10L] PnIA acted as an agonist. PnIA stabilized the receptor in a state that is non-conducting in both the wild type and mutant receptors, whereas [ A10L] PnIA stabilized a state that is non-conducting in the wild type receptor and conducting in the alpha7-L247T mutant. These data indicate that the change of a single amino acid side-chain, at position 10, is sufficient to change the toxin specificity for receptor states in the alpha7-L247T mutant.
Keyword Biochemistry & Molecular Biology
Neuronal Alpha(7)
Channel Domain
Allosteric Transitions
M2 Domain
Q-Index Code C1

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Created: Wed, 15 Aug 2007, 01:40:32 EST