Glutamate 172, essential for modulation of L247T alpha7 ACh receptors by Ca2+, lines the extracellular vestibule

Neuronal alpha7 nicotinic ACh receptors (nAChRs) are permeable to and modulated by Ca2+, Ba2+, and Sr2+. These permeant divalent cations interact with slowly desensitizing L247T alpha7 nAChRs to increase the potency and maximal efficacy of ACh, increase the efficacy of dihydro-beta-erythroidine (DHb...

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Bibliographic Details
Published in:American Journal of Physiology: Cell Physiology 2002-11, Vol.283 (5), p.C1454
Main Authors: Eddins, Donnie, Sproul, Adrian D, Lyford, Lisa K, McLaughlin, James T, Rosenberg, Robert L
Format: Article
Language:English
Subjects:
Acetylcholine - pharmacology
alpha7 Nicotinic Acetylcholine Receptor
Animals
Barium - pharmacokinetics
Calcium - metabolism
Cysteine - genetics
Extracellular Space
Glutamic Acid - genetics
Membrane Potentials - drug effects
Membrane Potentials - physiology
Mutagenesis - physiology
Oocytes - physiology
Patch-Clamp Techniques
Protein Structure, Tertiary
Receptors, Nicotinic - chemistry
Receptors, Nicotinic - genetics
Receptors, Nicotinic - metabolism
Strontium - pharmacokinetics
Water
Xenopus laevis
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Summary:Neuronal alpha7 nicotinic ACh receptors (nAChRs) are permeable to and modulated by Ca2+, Ba2+, and Sr2+. These permeant divalent cations interact with slowly desensitizing L247T alpha7 nAChRs to increase the potency and maximal efficacy of ACh, increase the efficacy of dihydro-beta-erythroidine (DHbetaE), and increase agonist-independent activity. Mutation of glutamate 172 (E172) to glutamine or cysteine eliminated these effects of permeant divalent cations. 2-(Trimethylammonium)ethyl methanethiosulfonate (MTSET), a cysteine-modifying reagent directed at water-accessible thiols, inhibited ACh-evoked currents of E172C/L247T alpha7 nAChRs by >90%, demonstrating that E172 was accessible to permeant ions. The data are consistent with a model of alpha7 receptors, derived from the crystal structure of the ACh binding protein (AChBP) from Lymnaea stagnalis, in which E172 projects toward the lumen of the extracellular vestibule. The observations that E172 was essential for divalent cation modulation of L247T alpha7 nAChRs and was accessible to permeating ions suggest that this residue participates in coupling ion permeation with modulation of receptor activity.
ISSN:0363-6143