Dataset Information

Lead poisoning: acute exposure of the heart to lead ions promotes changes in cardiac function and Cav1.2 ion channels.

ABSTRACT: Lead ions (Pb2+) possess characteristics similar to Ca2+. Because of this and its redox capabilities, lead causes different toxic effects. The neurotoxic effects have been well documented; however, the toxic effects on cardiac tissues remain allusive. We utilized isolated guinea pig hearts and measured the effects of Pb2+ on their contractility and excitability. Acute exposure to extracellular Pb2+ had a negative inotropic effect and increased diastolic tension. The speed of contraction and relaxation were affected, though the effects were more dramatic on the speed of contraction. Excitability was also altered. Heart beat frequency increased and later diminished after lead ion exposure. Pro-arrhytmic events, such as early after-depolarization and a reduction of the action potential plateau, were also observed. In isolated cardiomyocytes and tsA 201 cells, extracellular lead blocked currents through Cav1.2 channels, diminished their activation, and enhanced their fast inactivation, negatively affecting their gating currents. Thus, Pb2+ was cardiotoxic and reduced cardiac contractility, making the heart prone to arrhythmias. This was due, in part, to Pb2+ effects on the Cav1.2 channels; however, other channels, transporters or pathways may also be involved. Acute cardiotoxic effects were observed at Pb2+ concentrations achievable during acute lead poisoning. The results suggest how Cav1.2 gating can be affected by divalent cations, such as Pb2, and also suggest a more thorough evaluation of heart function in individuals affected by lead poisoning.

SUBMITTER: Ferreira de Mattos G

PROVIDER: S-EPMC5662044 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Lead poisoning: acute exposure of the heart to lead ions promotes changes in cardiac function and Cav1.2 ion channels.

Ferreira de Mattos Gonzalo G Costa Carlos C Savio Florencia F Alonso M M Nicolson G L GL

Biophysical reviews 20170823 5

Lead ions (Pb2+) possess characteristics similar to Ca2+. Because of this and its redox capabilities, lead causes different toxic effects. The neurotoxic effects have been well documented; however, the toxic effects on cardiac tissues remain allusive. We utilized isolated guinea pig hearts and measured the effects of Pb2+ on their contractility and excitability. Acute exposure to extracellular Pb2+ had a negative inotropic effect and increased diastoli ...[more]

PMID: 28836190

Similar Datasets

Project description:RationaleIn heart, Ca(2+) entering myocytes via Ca(V)1.2 channels controls essential functions, including excitation-contraction coupling, action potential duration, and gene expression. RGK GTPases (Rad/Rem/Rem2/Gem/Kir sub-family of Ras-like GTPases) potently inhibit Ca(V)1.2 channels, an effect that may figure prominently in cardiac Ca(2+) homeostasis under physiological and disease conditions.ObjectiveTo define the mechanisms and molecular determinants underlying Rem GTPase inhibition of Ca(V)1.2 channels in heart and to determine whether such inhibited channels can be pharmacologically rescued.Methods and resultsOverexpressing Rem in adult guinea pig heart cells dramatically depresses L-type calcium current (I(Ca,L)) ( approximately 90% inhibition) and moderately reduces maximum gating charge (Q(max)) (33%), without appreciably diminishing the physical number of channels in the membrane. Rem-inhibited Ca(V)1.2 channels were supramodulated by BAY K 8644 (10-fold increase) compared to control channels (3-fold increase). However, Rem prevented protein kinase A-mediated upregulation of I(Ca,L), an effect achieved without disrupting the sympathetic signaling cascade because protein kinase A modulation of I(KS) (slow component of the delayed rectifier potassium current) remained intact. In accord with its functional impact on I(Ca,L), Rem selectively prevented protein kinase A- but not BAY K 8644-induced prolongation of the cardiac action potential duration. A GTP-binding-deficient Rem[T94N] mutant was functionally inert with respect to I(Ca,L) inhibition. A chimeric construct, Rem(265)-H, featuring a swap of the Rem C-terminal tail for the analogous domain from H-Ras, inhibited I(Ca,L) and Q(max) to the same extent as wild-type Rem, despite lacking the capacity to autonomously localize to the sarcolemma.ConclusionsRem predominantly inhibits I(Ca,L) in heart by arresting surface Ca(V)1.2 channels in a low open probability gating mode, rather than by interfering with channel trafficking. Moreover, Rem-inhibited Ca(V)1.2 channels can be selectively rescued by BAY K 8644 but not protein kinase A-dependent phosphorylation. Contrary to findings in reconstituted systems, Rem-induced ablation of cardiac I(Ca,L) requires GTP-binding, but not membrane-targeting of the nucleotide binding domain. These findings provide a different perspective on the molecular mechanisms and structural determinants underlying RGK GTPase inhibition of Ca(V)1.2 channels in heart, and suggest new (patho)physiological dimensions of this crosstalk.

Dataset Information

Lead poisoning: acute exposure of the heart to lead ions promotes changes in cardiac function and Cav1.2 ion channels.

Publications

Lead poisoning: acute exposure of the heart to lead ions promotes changes in cardiac function and Cav1.2 ion channels.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets