Zn2+ current is mediated by voltage-gated Ca2+ channels and enhanced by extracellular acidity in mouse cortical neurones

1. Mammalian neuronal voltage-gated Ca2+ channels have been implicated as p otential mediators of membrane permeability to Zn2+. We tested directly whe ther voltage-gated Ca2+ channels can flux Zn2+ in whole-cell voltage-clamp recordings from cultured murine cortical neurones. 2. In the presence of extracellular Zn2+ and no Na+, K+, or other divalent cations, a small, noninactivating, voltage-gated inward current was observe d exhibiting a current-voltage relationship characteristic of high-voltage activated (HVA) Ca2+ channels. Inward current was detectable at Zn2+ levels as low as 50 muM, and both the amplitude and voltage sensitivity of the cu rrent depended upon Zn2+ concentration. This Zn2+ current was sensitive to blockade by Gd3+ and nimodipine and, to a lesser extent, by omega -conotoxi n GVIA. 3. Zn2+ could permeate Ca2+ channels in the presence of Ca2+ and other phys iological cations. Inward currents recorded with 2 mM Ca2+ were attenuated by Zn2+ (IC50 = 210 muM), and currents recorded with Zn2+ were unaffected I bly up to equimolar Ca2+ concentrations. Furthermore, the Zn2+-selective fl uorescent dye Newport Green revealed a depolarisation activated, nimodipine -sensitive Zn2+ influx into cortical neurones that were bathed in a physiol ogical extracellular solution plus 300 muM ZnCl2. 4. Surprisingly, while lowering extracellular pH suppressed HVA Ca2+ curren ts, Zn2+ current amplitude was affected oppositely, varying inversely with pH with an apparent pK of 7.4. The acidity-induced enhancement of Zn2+ curr ent was associated with a positive shift in reversal potential but no chang e in the kinetics or voltage sensitivity of channel activation. 5. These results provide evidence that L- and N-type voltage-gated Ca2+ cha nnels can mediate Zn2+ entry into cortical neurones and that this entry may be enhanced by extracellular acidity.