Lead exerts a depression of neurotransmitter release through a blockade of voltage dependent calcium channels in chromaffin cells

Victoria Jiménez Carretero; Ninfa Liccardi; Maria Arribas Tejedor; Ricardo de Pascual; Jorge Hernández Campano; Jesús M Hernández-Guijo

doi:10.1016/j.tox.2024.153809

Lead exerts a depression of neurotransmitter release through a blockade of voltage dependent calcium channels in chromaffin cells

Toxicology. 2024 Apr 20:505:153809. doi: 10.1016/j.tox.2024.153809. Online ahead of print.

Authors

Victoria Jiménez Carretero¹, Ninfa Liccardi¹, Maria Arribas Tejedor¹, Ricardo de Pascual¹, Jorge Hernández Campano¹, Jesús M Hernández-Guijo²

Affiliations

¹ Department of Pharmacology and Therapeutic, Facultad de Medicina, Univ. Autónoma de Madrid, Av. Arzobispo Morcillo 4, Madrid 28029, Spain.
² Department of Pharmacology and Therapeutic, Facultad de Medicina, Univ. Autónoma de Madrid, Av. Arzobispo Morcillo 4, Madrid 28029, Spain; Ramón y Cajal Institute for Health Research, IRYCIS, Hospital Ramón y Cajal, Ctra. de Colmenar Viejo, Km. 9,100, Madrid 28029, Spain. Electronic address: jesusmiguel.hernandez@uam.es.

PMID: 38648961
DOI: 10.1016/j.tox.2024.153809

Abstract

The present work, using chromaffin cells of bovine adrenal medullae (BCCs), aims to describe what type of ionic current alterations induced by lead (Pb²⁺) underlies its effects reported on synaptic transmission. We observed that the acute application of Pb²⁺ lead to a drastic depression of neurotransmitters release in a concentration-dependent manner when the cells were stimulated with both K⁺ or acetylcholine, with an IC₅₀ of 119,57 μM and of 5,19 μM, respectively. This effect was fully recovered after washout. Pb²⁺ also blocked calcium channels of BCCs in a time- and concentration-dependent manner with an IC₅₀ of 6,87 μM. This blockade was partially reversed upon washout. This compound inhibited the calcium current at all test potentials and shows a shift of the I-V curve to more negative values of about 8 mV. The sodium current was not blocked by acute application of high Pb²⁺ concentrations. Voltage-dependent potassium current was also shortly affected by high Pb²⁺. Nevertheless, the calcium- and voltage-dependent potassium current was drastically depressed in a dose-dependent manner, with an IC₅₀ of 24,49 μM. This blockade was related to the prevention of Ca²⁺ influx through voltage-dependent calcium channels coupled to Ca²⁺-activated K⁺-channels (BK) instead a direct linking to these channels. Under current-clamp conditions, BCCs exhibit a resting potential of -52.7 mV, firing spontaneous APs (1-2 spikes/s) generated by the opening of Na⁺ and Ca²⁺-channels, and terminated by the activation of K⁺ channels. In spite of the effect on ionic channels exerted by Pb²⁺, we found that Pb²⁺ didn't alter cellular excitability, no modification of the membrane potential, and no effect on action potential firing. Taken together, these results point to a neurotoxic action evoked by Pb²⁺ that is associated with changes in neurotransmitter release by blocking the ionic currents responsible for the calcium influx.

Keywords: Calcium channels; Catecholamines; Cellular excitability; Chromaffin cells; Lead; Neurotransmitter release.