TY - JOUR
T1 - Modulation of neuronal nicotinic acetylcholine receptors by mercury
AU - Mirzoian, Armen
AU - Luetje, Charles W.
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2002
Y1 - 2002
N2 - Mercuric chloride exerted a biphasic modulatory effect on rat neuronal nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus laevis oocytes as heteromers of the α3 or α4 and β2 or β4 subunits. The degree of modulation was subunit-dependent, with β4-containing receptors displaying greater potentiation and α4-containing receptors displaying greater inhibition. Thus, α4β4 receptors displayed both robust potentiation and robust inhibition. During prolonged coapplication of HgCl2, first potentiation then inhibition of the acetylcholine (ACh) response was observed. Upon coapplication of 1 μM HgCl2, a 2-fold increase in ACh-induced current was achieved in 55 ± 1 s. With continued HgCl2 application, the ACh response was slowly inhibited until, after 5 min, less than 10% of the initial response remained. By measuring potentiation at its peak and inhibition 5 min after the start of HgCl2 coapplication, we obtained EC50 and IC50 values of 262 ± 75 and 430 ± 72 nM, respectively. HgCl2 potentiation was voltage-dependent, increasing at more positive holding potentials. Upon washout of mercury chloride, potentiation reversed with a t1/2 of 4.6 min. Inhibition reversed more slowly, with less than half the initial response recovered after 15 min of wash. Although free cysteine residues are common targets for mercury, elimination of all free cysteines located in the extracellular domains of the α4 and β4 subunits did not alter the effects of mercuric chloride. Potentiation and inhibition of neuronal nAChRs may occur through action at a transmembrane or cytoplasmic location after passive diffusion of mercuric chloride across the plasma membrane.
AB - Mercuric chloride exerted a biphasic modulatory effect on rat neuronal nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus laevis oocytes as heteromers of the α3 or α4 and β2 or β4 subunits. The degree of modulation was subunit-dependent, with β4-containing receptors displaying greater potentiation and α4-containing receptors displaying greater inhibition. Thus, α4β4 receptors displayed both robust potentiation and robust inhibition. During prolonged coapplication of HgCl2, first potentiation then inhibition of the acetylcholine (ACh) response was observed. Upon coapplication of 1 μM HgCl2, a 2-fold increase in ACh-induced current was achieved in 55 ± 1 s. With continued HgCl2 application, the ACh response was slowly inhibited until, after 5 min, less than 10% of the initial response remained. By measuring potentiation at its peak and inhibition 5 min after the start of HgCl2 coapplication, we obtained EC50 and IC50 values of 262 ± 75 and 430 ± 72 nM, respectively. HgCl2 potentiation was voltage-dependent, increasing at more positive holding potentials. Upon washout of mercury chloride, potentiation reversed with a t1/2 of 4.6 min. Inhibition reversed more slowly, with less than half the initial response recovered after 15 min of wash. Although free cysteine residues are common targets for mercury, elimination of all free cysteines located in the extracellular domains of the α4 and β4 subunits did not alter the effects of mercuric chloride. Potentiation and inhibition of neuronal nAChRs may occur through action at a transmembrane or cytoplasmic location after passive diffusion of mercuric chloride across the plasma membrane.
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U2 - 10.1124/jpet.102.035154
DO - 10.1124/jpet.102.035154
M3 - Article
C2 - 12130716
AN - SCOPUS:0036070699
VL - 302
SP - 560
EP - 567
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
SN - 0022-3565
IS - 2
ER -