Characteristics of the methylmercury-induced decrease of whole cell barium current in cerebellar granule neurons

Methylmercury (MeHg) is an organomercurial compound which preferentially disrupts granuie cells of the cerebellum. To examine a possible mechanism which may contribute to the sensitivity of granule cells to MeHg, whole cell barium (Ba{dollar}sp{lcub}2+{rcub}{dollar}) currents were measured in primary cultures of cerebellar granule cells in the presence and absence of MeHg. 0.25-1 {dollar}mu{dollar}M MeHg decreased Ba{dollar}sp{lcub}2+{rcub}{dollar} currents irreversibly, in a concentration- and time-dependent fashion. Following exposure to 0.25, and in some cases 0.5, pM MeHg in the absence of depolanzing stimuli, current at the end of the voltage step was decreased to a greater degree than peak current. At 1 {dollar}mu{dollar}M MeHg, peak and end currents were reduced an equal amount in the absence of depolarizing stimuli. Increasing the stimulation frequency from 0.1 to 0.2 Hz facilitated the reduction in current by 0.25 and 0.5 {dollar}mu{dollar}M MeHg, but not 1 {dollar}mu{dollar}M MeHg.; Several peptide toxins and a dihydropyridine compound were used to examine the role of Ca{dollar}sp{lcub}2+{rcub}{dollar} channel subtypes in the MeHg-induced decrease of whole cell Ba{dollar}sp{lcub}2+{rcub}{dollar} current. Perfusion of these compounds prior to MeHg exposure did not prevent MeHg from decreasing whole cell Ba{dollar}sp{lcub}2+{rcub}{dollar} current. When nimodipine or calcicludine were added prior to MeHg, the subsequent decrease in peak Ba{dollar}sp{lcub}2+{rcub}{dollar} current produced by MeHg was greater than that seen with MeHg alone. Perfusion of GVIA or MVIIC following removal of a portion of the whole cell Ba{dollar}sp{lcub}2+{rcub}{dollar} current by MeHg resulted in an initial apparent rate of decline of the remaining current that was similar to the rate observed in the absence of MeHg. Addition of nimodipine in the presence of MeHg did not alter the apparent MeHg-induced rate of current reduction, suggesting that reductions in Ba{dollar}sp{lcub}2+{rcub}{dollar} current produced these two agents was not additive. Thus, cerebellar granule cell Ca{dollar}sp{lcub}2+{rcub}{dollar} channels are sensitive to micromolar concentrations of MeHg. The results are consistent with an ability of MeHg to decrease current through all Ca{dollar}sp{lcub}2+{rcub}{dollar} channel subtypes.