Effects of charge and lipophilicity on mercurial-induced reduction of 45Ca2+ uptake in isolated nerve terminals of the rat

Sandra J. Hewett, William D. Atchison

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

The goal of this study was to compare the ability of neurotoxic mercurials which differ in ionic charge and/or lipophilicity to block nerve-terminal calcium channels. To do so, we examined the acute effects of methyl mercury (MeHg+), ethyl mercury (EtHg+), inorganic mercury (Hg2+), dimethyl mercury (Me2Hg), p-chloromercuribenzoate (PCMB), and p-chloromercuriphenylsulfonate (PCMBS-) (10-1000 μm) on 45Ca2+ flux into rat forebrain synaptosomes at rest and during depolarization. Basal (depolarization-independent) entry of 45Ca2+ was measured during 10-sec exposure to mercurials in solutions containing 5 mm KCl. Concentrations of 50, 100, 250, 500, and 1000 μm of Hg2+, MeHg+, and EtHg+ reduced basal influx of 45Ca2+. PCMB reduced basal influx at concentrations of 10, 50, and 100 μm, but increased influx at 1000 μm. PCMBS- and (Me)2Hg had no effect on basal flux at any concentration tested. Uptake of 45Ca2+ was measured after 1 sec of K+-induced depolarization (41.25 mm) to determine influx through voltage-dependent Ca2+ channels ("fast" phase) or during the last 10 sec of a 20-sec period of depolarization for uptake associated with a reversed Na+ Ca2+ exchanger and a residual noninactivating Ca2+ channel component ("slow" phase). Fast and slow components of 45Ca2+ uptake into synaptosomes were blocked in a concentration-dependent manner by MeHg+, EtHg+, and Hg2+. For block of the fast component, the calculated IC50's and confidence intervals were (μm) EtHg+, 92 (82, 102); Hg2+, 155 (149, 161); and MeHg+, 196 (120, 272). IC50's and the confidence intervals for the slow component of uptake were (μm) Hg2+, 49 (43, 55); MeHg+, 72 (67, 77); and EtHg+, 147 (142, 152). In contrast, Me2Hg, PCMB, and PCMBS- (10-1000 μm) caused no appreciable reduction in either phase of 45Ca2+ uptake. Increasing [Ca2+]e was unable to overcome the block induced by MeHg+ and EtHg+ (100 μm) on either phase of 45Ca2+ uptake into synaptosomes. Likewise, increasing [Ca2+]e failed to overcome block of the slow component by Hg2+ (100 μm). Increasing [Ca2+]e was able to overcome, in part, block of the fast phase induced by Hg2+ (100 μm) although the percentage of reversal was not statistically significant. The magnitude of block of 45Ca2+ uptake increased as a function of increasing [K+]e for MeHg+ and EtHg+, suggesting the block to be voltage-dependent. Thus, mercurials of dissimilar charge and lipophilicity affect synaptosomal Ca2+ uptake differentially. Specifically, results of this study suggest that: (1) high concentrations of certain mercurials affect resting Ca2+ permeability; (2) a positive charge is important for interaction of mercurials with Ca2+ channels during depolarization; (3) organic, monovalent mercurials block influx of 45Ca2+ into synaptosomes in a noncompetitive, voltage-dependent manner; and (4) divalent mercury blocks influx of 45Ca2+ into synaptosomes in a competitive, voltage-independent manner.

Original languageEnglish (US)
Pages (from-to)267-273
Number of pages7
JournalToxicology and Applied Pharmacology
Volume113
Issue number2
DOIs
StatePublished - Apr 1992
Externally publishedYes

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology

Fingerprint Dive into the research topics of 'Effects of charge and lipophilicity on mercurial-induced reduction of <sup>45</sup>Ca<sup>2+</sup> uptake in isolated nerve terminals of the rat'. Together they form a unique fingerprint.

  • Cite this