Permeant but not impermeant divalent cations enhance activation of nondesensitizing α7 nicotinic receptors

Neuronal α7 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) α7 nAChRs by permeant (Ca2+, Ba2+, and Sr2+) and impermeant (Cd2+ and Zn2+) divalent cations. α7 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-β-erythroidine (DHβE) was a strong partial agonist of L247T and S240T/L247T α7 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 α7 nAChRs eliminated Ca2+conductance but did not alter the Ca2+-dependent increase in ACh potency, suggesting that site(s) required for modulation are on...