DEPENDENCE OF SINGLE-CHANNEL PROPERTIES OF THE N-METHYL-D-ASPARTATE ION-CHANNEL ON STEREOISOMER AGONISTS

The cell-attached patch-clamp configuration has been used to determine the single channel properties of the N-methyl-D-aspartate (NMDA) ion channel with activation of the NMDA receptor by stereoisomer agonists. All of the agonists studied, including the L and D forms of N-methyl- aspartate and the L and D forms of homocysteate, activated a 42-pS con ductance channel in cultured hippocampal neurons. For all agonists, th e mean open times of the channel were diminished with increased patch hyperpolarization and exhibited an exponential dependence on potential over the range -40 mV to - 120 mV. The mean open times, for patch pot entials close to resting potential, and the mean frequencies of channe l openings, at all patch potentials, were significantly different betw een each member of the stereoisomer pairs. For both L-homocysteate and NMLA, a four-fold increase in the patch pipette concentration caused an approximate quadrupling in the frequency of unitary events, with no significant change in mean open time. The open channel probability wa s used as a measure of agonist potency, and, at a concentration of 30 muM, NMDA and L-homocysteate were significantly more potent (P open in excess of 1.5%) than the corresponding stereoisomer compounds NMLA an d D-homocysteate (P open near 0.3%). The relative potencies of the ste reoisomer pairs were in reasonable agreement with the potency ratios m easured in binding studies.