Zinc inhibits miniature GABAergic currents by allosteric modulation of GABA(A) receptor gating

Zinc is abundantly present in the CNS, and after nerve stimulation is thoug ht to be released in sufficient quantity to modulate the synaptic transmiss ion. Although it is known that this divalent cation inhibits the GABAergic synaptic currents, the underlying mechanisms were not fully elucidated. Her e we report that zinc reduced the amplitude, slowed the rise time, and acce lerated the decay of mIPSCs in cultured hippocampal neurons. The analysis o f current responses to rapid GABA applications and model simulations indica ted that these effects on mIPSCs are caused by zinc modulation of GABA(A) r eceptor gating. In particular, zinc slowed the onset of GABA-evoked current s by decreasing both the binding (k(on)) and the transition rate from close d to open state (beta (2)). Moreover, slower onset and recovery from desens itization as well as an increased unbinding rate (k(off)) were shown to und erlie the accelerated deactivation kinetics in the presence of zinc. The no nequilibrium conditions of GABA(A) receptor activation were found to strong ly affect zinc modulation of this receptor. In particular, an extremely fas t clearance of synaptic GABA is implicated to be responsible for a stronger zinc effect on mIPSCs than on current responses to exogenous GABA. Finally , the analysis of currents evoked by GABA coapplied with zinc indicated tha t the interaction between zinc and GABA(A) receptors was too slow to explai n zinc effects in terms of competitive antagonism. In conclusion, our resul ts provide evidence that inhibition of mIPSCs by zinc is attributable to th e allosteric modulation of GABA(A) receptor gating.