Pathways of Cadmium Influx in Mammalian Neurons

Abstract

The Influx of the toxic cation Cd²⁺ was studied in fura 2‐loaded rat cerebellar granule neurons. In cells depolarized with Ca²⁺‐free, high‐KCI solutions, the fluorescence emission ratio (R) increased in the presence of 100 γM Cd²⁺. This increase was fully reversed by the Cd²⁺ chelator tetrakis(2‐pyridylmethyl)ethylenediamine, indicating a cadmium influx into the cell. The rate of increase, dR/dt, was greatly reduced (67 ± 5%) by 1 γM nimodipine and enhanced by 1 γM Bay K 8644. Concurrent application of nimodipine and ω‐agatoxin IVA (200 nM) blocked Cd2+ permeation almost completely (88 ± 5%), whereas ω‐conotoxin MVIIC (2 γM) reduced dR/dt by 24 ± 8%. These results indicate a primary role of voltage‐dependent calcium channels in Cd2+ permeation. Stimulation with glutamate or NMDA and glycine also caused a rise of R in external Cd²⁺. Simultaneous application of nimodipine and ω‐agatoxin IVA moderately reduced dR/dt (25 ± 3%). NMDA‐driven Cd²⁺ entry was almost completely prevented by 1 mM Mg²⁺, 50 γM memantine, and 10 γM 5,7‐dichlorokynurenic acid, suggesting a major contribution of NMDA‐gated channels in glutamate‐stimulated Cd²⁺ influx. Moreover, perfusion with α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate caused a slow increase of R. These results suggest that Cd²⁺ permeates the cell membrane mainly through the same pathways of Ca²⁺ influx.