Modulation of Neuronal Nicotinic Acetylcholine Receptors by Mercury

Abstract

Mercuric chloride exerted a biphasic modulatory effect on rat neuronal nicotinic acetylcholine receptors (nAChRs) expressed in Xenopus laevis oocytes as heteromers of the ␣3 or ␣4 and ␤2 or ␤4 subunits. The degree of modulation was subunit-dependent, with ␤4-containing receptors displaying greater potentiation and ␣4-containing receptors displaying greater inhibition. Thus, ␣4␤4 receptors displayed both robust potentiation and robust inhibition. During prolonged coapplication of HgCl 2 , first potentiation then inhibition of the acetylcholine (ACh) response was observed. Upon coapplication of 1 M HgCl 2 , a 2-fold increase in ACh-induced current was achieved in 55 Ϯ 1 s. With continued HgCl 2 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 HgCl 2 coapplication, we obtained EC 50 and IC 50 values of 262 Ϯ 75 and 430 Ϯ 72 nM, respectively. HgCl 2 potentiation was voltage-dependent, increasing at more positive holding potentials. Upon washout of mercury chloride, potentiation reversed with a t 1/2 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 ␣4 and ␤4 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.

Reactive Oxygen Species Potentiate the P2X2Receptor Activity through Intracellular Cys430

“…Receptor recycling and trafficking of new synthesized receptors might also contribute in part to the recovery of basal receptor activity. Mirzoian and Luetje (2002) also discussed that the effect of mercury chloride on nicotinic receptors reversed slowly, persisting for several minutes after washout. In addition, the effects of mercury are described as slowly reversible or, in other cases, irreversible in several ionic channels and receptors (Gallagher et al, 1995; Huang and Narahashi, 1996; Mirzoian and Luetje, 2002).…”

Perioral Dermatitis after Dental Filling in a 12-Year-Old Girl: Involvement of Cholinergic System in Skin Neuroinflammation?

“…Furthermore, methylmercury (highly reactive) can interact with receptors, channels, and enzymes, damaging neuronal membrane functionality and excitability [24]. Indeed, studies show that several types of cholinergic receptors and/or pathways are directly affected by mercury compounds [25]; for example, methylmercury blocks the binding of acetylcholine to the cholinergic nicotinic receptor of the electric organ of Torpedo californica [26]. Also, in T. californica, organomercurials can block the activity of the vesicular acetylcholine transporter (VAchT), an enzyme that concentrates acetylcholine in secretory vesicles [27].…”

Mechanisms of cholinesterase inhibition by inorganic mercury

“…Nephrotoxicity [4] and genotoxicity [5] have been demonstrated. Other adverse effects occur in neural tissues, where the targeting of enzymes and receptors involved in nerve impulse transmission is probably involved [6], as well as in the immune system, for which both autoimmunity and immune suppression have been reported [7–9]. Detection of mercury in the environment is thus of high relevance for public health and in the framework of sustainable development.…”