Voltage and concentration dependence of Ca2+ permeability in recombinant glutamate receptor subtypes

The channels associated with glutamate receptor (GluR) subtypes, namely N-methyl-D-aspartate receptors (NMDARs), and Ca2+-permeable alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptors (AMPARs) and kainate receptors (KARs), are to varying degrees permeable to Ca2+. To compare the mechanism of Ca2+ influx, we measured Ca2+ permeability relative to that of Na+ (P-Ca/P-Na) using fractional Ca2+ currents (P-f) and reversal potential measurements over a wide voltage and Ca2+ concentration range in recombinant NMDAR NR1-NR2A, AMPAR GluR-A(Q) and KAR GluR-6(Q) channels. For NR1-NR2A channels, P-Ca/P-Na derived from P-f measurements was voltage independent but showed a weak concentration dependence. A stronger concentration dependence was found when P-Ca/P-Na was derived from changes in reversal potentials on going from a Na+ reference solution to a solution with Ca2+ as the only permeant ion (`biionic' condition). In contrast, P-Ca/P-Na was concentration independent when derived from changes in reversal potentials on going from a Na+ reference solution to the same solution with added Ca2+ (`high monovalent' condition). For GluR-A(Q) channels, P-Ca/P-Na derived from all three approaches was concentration independent, and for the reversal potential-based approaches were of comparable magnitude. Their most distinctive property was that P-Ca/P-Na derived from P-f measurements was strongly voltage dependent. For GluR-6(Q) channels, P-Ca/P-Na derived from P-f measurements was weakly voltage dependent. On the other hand, P-Ca/P-Na derived from all three approaches was the most strongly concentration dependent of any GluR subtype and, except for low Ca+ concentrations, the values were of comparable magnitude. Thus, the three Ca2+ -permeable GluR subtypes showed unique patterns of Ca2+ permeability, indicating that distinct biophysical and molecular events underlie Ca2+ influx in each subtype.