Permeant but not impermeant divalent cations enhance activation of nondesensitizing alpha(7) nicotinic receptors.
Neuronal alpha(7) nicotinic acetylcholine receptors (nAChRs) are permeable to Ca(2+) and other divalent cations. We characterized the modulation of the pharmacological properties of nondesensitizing mutant (L(247)T and S(240)T/L(247)T) alpha(7) nAChRs by permeant (Ca(2+), Ba(2+), and Sr(2+)) and impermeant (Cd(2+) and Zn(2+)) 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 (DHbetaE) was a strong partial agonist of L(247)T and S(240)T/L(247)T 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 (E(237)A) in L(247)T alpha(7) nAChRs eliminated Ca(2+) conductance but did not alter the Ca(2+)-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.
Eddins
Donnie
D
Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Lyford
Lisa K
LK
Lee
Jung Weon
JW
Desai
Sanjay A
SA
Rosenberg
Robert L
RL
D000109:Acetylcholine / Q000494:pharmacology; D000157:Aconitine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001464:Barium / Q000493:pharmacokinetics; D002104:Cadmium / Q000494:pharmacology; D002118:Calcium / Q000493:pharmacokinetics*; D002413:Cations, Divalent / Q000378:metabolism; D002642:Chick Embryo; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D007306:Insecticides / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D008274:Magnesium / Q000493:pharmacokinetics; D016297:Mutagenesis, Site-Directed / Q000502:physiology; D009865:Oocytes / Q000502:physiology; D011978:Receptors, Nicotinic / Q000235:genetics* / Q000378:metabolism*; D013324:Strontium / Q000493:pharmacokinetics; D014981:Xenopus; D015032:Zinc / Q000494:pharmacology; D064569:alpha7 Nicotinic Acetylcholine Receptor
D002413:Cations, Divalent; D007306:Insecticides; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D002104:Cadmium; C054634:methyllycaconitine; D004079:Dihydro-beta-Erythroidine; D001464:Barium; D008274:Magnesium; D015032:Zinc; D000109:Acetylcholine; D002118:Calcium; D000157:Aconitine; D013324:Strontium