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First published online on September 13, 2002.
 Copyright © 2002 by The Physiological Society
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2002.029413v1
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Received July 24, 2002
Accepted after revision August 6, 2002

Contributions of the non-{alpha} subunit residues (loop D) to agonist binding and channel gating in the muscle nicotinic acetylcholine receptor

G. Akk1*

1 Department of Anesthesiology, Washington University School of Medicine, Campus Box 8054, 660 South Euclid Ave, St Louis, MO 63110, USA

* To whom correspondence should be addressed. E-mail: akk{at}morpheus.wustl.edu.

The agonist binding site of the nicotinic acetylcholine receptor has a loop-based structure, and is formed by residues located remotely to each other in terms of primary structure. Amino acid residues in sites d[%%%]57 and d[%%%]59, and the equivalent residues in the {epsilon} subunit, have been identified as part of the agonist binding site and designated as loop D. The effects of point mutations in sites d[%%%]57, d[%%%]59, {epsilon}55 and {epsilon}57 on agonist binding and channel gating were studied. The mutated receptors were expressed transiently in HEK 293 cells and the currents were recorded using the cell-attached single-channel patch clamp technique. The results demonstrate that the mutations mainly affect channel gating with the major portion of the effect due to a reduction in the channel opening rate constant. For both the d[%%%]57/{epsilon}55 and the d[%%%]59/{epsilon}57 site, a mutation in the {epsilon} subunit had a greater effect on channel gating than a mutation in the d[%%%] subunit. In all instances, agonist binding was affected to a lesser degree than channel gating. Previous data have placed the d[%%%]57 and d[%%%]59 residues in or near the agonist binding pocket. The data presented here suggest that these two residues (and the homologous sites in the {epsilon} subunit) are not involved in specific interactions with the nicotinic agonist and that they affect the activation of the nicotinic receptor by shaping the overall structure of the agonist binding site.




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