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Am J Physiol Cell Physiol (November 14, 2001). doi:10.1152/ajpcell.00453.2001
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Articles in PresS, published online ahead of print November 13, 2001
Am J Physiol Cell Physiol, 10.1152/ajpcell.00453.2001
Submitted on September 21, 2001
Accepted on November 9, 2001

Permeant but not impermeant divalent cations enhance the activation of non-desensitizing {alpha}7 nicotinic receptors

Donnie Eddins1, Lisa K Lyford1, Jung Weon Lee1, Sanjay A Desai2, and Robert L Rosenberg3*

1 Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
2 National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA
3 Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Cell & 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 acetylcholine receptors (nAChRs) are permeable to Ca2+ and other divalent cations. We characterized the modulation of the pharmacological properties of non-desensitizing 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-ß-erythroidine (DHßE) was a strong partial agonist of L247T and S240T/L247T {alpha}7 receptors in the presence of permeant divalent cations, but was a weak partial agonist in the presence of impermeant divalents. 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.




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