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Am J Physiol Cell Physiol 282: C796-C804, 2002. First published November 14, 2001; doi:10.1152/ajpcell.00453.2001
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Vol. 282, Issue 4, C796-C804, April 2002

Permeant but not impermeant divalent cations enhance activation of nondesensitizing alpha 7 nicotinic receptors

Donnie Eddins1, Lisa K. Lyford1, Jung Weon Lee1, Sanjay A. Desai3, and Robert L. Rosenberg1,2

Departments of 1 Pharmacology and 2 Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599; and 3 Division of Infectious Diseases and International Health, Duke University, Durham, North Carolina 27710

Neuronal alpha 7 nicotinic acetylcholine receptors (nAChRs) are permeable to Ca2+ and other divalent cations. We characterized the modulation of the pharmacological properties of nondesensitizing mutant (L247T and S240T/L247T) alpha 7 nAChRs by permeant (Ca2+, Ba2+, and Sr2+) and impermeant (Cd2+ and Zn2+) divalent cations. alpha 7 receptors were expressed in Xenopus oocytes and studied with two-electrode voltage clamp. Extracellular permeant divalent cations increased the potency and maximal efficacy of ACh, whereas impermeant divalent cations decreased potency and maximal efficacy. The antagonist dihydro-beta -erythroidine (DHbeta E) was a strong partial agonist of L247T and S240T/L247T alpha 7 receptors in the presence of divalent cations but was a weak partial agonist in the presence of impermeant divalent cations. Mutation of the "intermediate ring" glutamates (E237A) in L247T alpha 7 nAChRs eliminated Ca2+ conductance but did not alter the Ca2+-dependent increase in ACh potency, suggesting that site(s) required for modulation are on the extracellular side of the intermediate ring. The difference between permeant and impermeant divalent cations suggests that sites within the pore are important for modulation by divalent cations.

acetylcholine receptor; calcium; M2 domain; potency; permeation


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