Aluminum alters excitability by inhibiting calcium, sodium, and potassium currents in bovine chromaffin cells

Abstract

Aluminum (Al³⁺ ) has long been related to neurotoxicity and neurological diseases. This study aims to describe the specific actions of this metal on cellular excitability and neurotransmitter release in primary culture of bovine chromaffin cells. Using voltage-clamp and current-clamp recordings with the whole-cell configuration of the patch clamp technique, online measurement of catecholamine release, and measurements of [Ca²⁺ ]_c with Fluo-4-AM, we have observed that Al³⁺ reduced intracellular calcium concentrations around 25% and decreased catecholamine secretion in a dose-dependent manner, with an IC₅₀ of 89.1 μM. Al³⁺ blocked calcium currents in a time- and concentration-dependent manner with an IC₅₀ of 560 μM. This blockade was irreversible since it did not recover after washout. Moreover, Al³⁺ produced a bigger blockade on N-, P-, and Q-type calcium channels subtypes (69.5%) than on L-type channels subtypes (50.5%). Sodium currents were also inhibited by Al³⁺ in a time- and concentration-dependent manner, 24.3% blockade at the closest concentration to the IC₅₀ (399 μM). This inhibition was reversible. Voltage-dependent potassium currents were low affected by Al³⁺ . Nonetheless, calcium/voltage-dependent potassium currents were inhibited in a concentration-dependent manner, with an IC₅₀ of 447 μM. This inhibition was related to the depression of calcium influx through voltage-dependent calcium channels subtypes coupled to BK channels. In summary, the blockade of these ionic conductance altered cellular excitability that reduced the action potentials firing and so, the neurotransmitter release and the synaptic transmission. These findings prove that aluminum has neurotoxic properties because it alters neuronal excitability by inhibiting the sodium currents responsible for the generation and propagation of impulse nerve, the potassium current responsible for the termination of action potentials, and the calcium current responsible for the neurotransmitters release.

Keywords: aluminum; calcium currents; chromaffin cells; neurotransmitter release; potassium currents; sodium currents.