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Am J Physiol Cell Physiol (July 17, 2002). doi:10.1152/ajpcell.00204.2002
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Articles in PresS, published online ahead of print July 17, 2002
Am J Physiol Cell Physiol, 10.1152/ajpcell.00204.2002
Submitted on May 3, 2002
Accepted on July 16, 2002

Glutamate 172, essential for modulation of L247T {alpha}7 ACh receptors by Ca2+, lines the extracellular vestibule

Donnie Eddins1, Adrian D. Sproul1, Lisa K. Lyford1, James T. McLaughlin1, and Robert L. Rosenberg2*

1 Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
2 Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

* To whom correspondence should be addressed. E-mail: bobr{at}med.unc.edu.

Neuronal {alpha}7 nicotinic ACh receptors (nAChRs) are permeable to and modulated by Ca2+, Ba2+, and Sr2+. These permeant divalent cations interact with slowly-desensitizing L247T {alpha}7 nAChRs to increase the potency and maximal efficacy of ACh, increase the efficacy of dihydo-ß-erythroidine (DHßE), and increase agonist-independent activity. Mutation of glutamate 172 to glutamine or cysteine eliminated these effects of permeant divalent cations. MTSET, cysteine-modifying reagent directed at water-accessible thiols, inhibited ACh-evoked currents of E172C/L247T {alpha}7 nAChRs by >90%, demonstrating that E172 was accessible to permeant ions. The data are consistent with a model of {alpha}7 receptors, derived from the crystal structure of the ACh binding protein (AChBP) from Lymnaea stagnalis, in which E172 projects towards the lumen of the extracellular vestibule. The observations that E172 was essential for divalent cation modulation of L247T {alpha}7 nAChRs and was accessible to permeating ions suggest that this residue participates in coupling ion permeation with modulation of receptor activity.




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[Abstract] [Full Text] [PDF]


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