Pathways of cadmium influx in mammalian neurons

The influx of the toxic cation Cd2+ was studied in fura 2-loaded rat cerebe llar granule neurons. in cells depolarized with Ca2+-free, high-KCl solutio ns, the fluorescence emission ratio (R) increased in the presence of 100 mu M Cd2+. This increase was fully reversed by the Cd2+ chelator tetrakis(2-p yridylmethyl)ethylenediamine indicating a cadmium influx into the cell. The rate of increase, dR/dt, was greatly reduced (67 +/- 5%) by 1 mu M nimodip ine and enhanced by 1 mu M Bay K 8644, Concurrent application of nimodipine and omega-agatoxin IVA (200 nM) blocked Cd2+ permeation almost completely (88 +/- 5%), whereas omega-conotoxin MVIIC (2 mu M) reduced dR/dt by 24 +/- 8%, These results indicate a primary role of voltage-dependent calcium cha nnels in Cd2+ permeation. Stimulation with glutamate or NMDA and glycine al so caused a rise of R in external Cd2+. Simultaneous application of nimodip ine and omega-agatoxin IVA moderately reduced dR/dt (25 +/- 3%). NMDA-drive n Cd2+ entry was almost completely prevented by 1 mM Mg2+, 50 mu M memantin e, and 10 mu M 5,7-dichlorokynurenic acid, suggesting a major contribution of NMDA-gated channels in glutamate-stimulated Cd2+ influx. Moreover, perfu sion with alpha-amino 3-hydroxy-5-methylisoxazole-4-propionate caused a slo w increase of R. These results suggest that Cd2+ permeates the cell membran e mainly through the same pathways of Ca2+ influx.