The Journal of Neurophysiology Vol. 87 No. 6 June 2002, pp. 2983-2989
Copyright ©2002 by the American Physiological Society

K⁺ Currents Generated by NMDA Receptor Activation in Rat Hippocampal Pyramidal Neurons

Department of Pharmacology, University College London, London WC1E 6BT, United Kingdom

Shah, Mala M. and Dennis G. Haylett. K⁺ Currents Generated by NMDA Receptor Activation in Rat Hippocampal Pyramidal Neurons. J. Neurophysiol. 87: 2983-2989, 2002. Long lasting outward currents mediated by Ca²⁺-activated K⁺ channels can be induced by Ca²⁺ influx through N-methyl-D-aspartate (NMDA)-receptor channels in voltage-clamped hippocampal pyramidal neurons. Using specific inhibitors, we have attempted to identify the channels that underlie these outward currents. At a holding potential of 50 mV, applications of 1 mM NMDA to the soma of cultured hippocampal pyramidal neurons induced the expected inward currents. In 44% of cells tested, these were followed by outward currents (average amplitude 60 ± 7 pA) that peaked 2.5 s after the initiation of the inward NMDA currents and decayed with a time constant of 1.4 s. In 43% of those cells exhibiting an outward current, SK channel inhibitors, UCL 1848 (100 nM) and apamin (100 nM) abolished the outward current. In the remainder of the cells, the outward currents were either insensitive or only partly inhibited (44 ± 4%) by 100 nM UCL 1848. In these cells, the outward currents were reduced by the slow afterhyperpolarization (sAHP) inhibitors, muscarine (3 µM; 43 ± 9%), UCL 1880 (3 µM; 34 ± 10%), and UCL 2027 (3 µM; 57 ± 6%). Neither the BK channel inhibitor, charybdotoxin (100 nM), nor the Na⁺/K⁺ ATPase inhibitor, ouabain (100 µM), reduced these outward currents. Irrespective of the pharmacology, the time course of the outward current did not differ. Interestingly, no correlation was observed between the presence of a slow apamin-insensitive afterhyperpolarization and an outward current insensitive to SK channel blockers following NMDA-receptor activation. It is concluded that an NMDA-mediated rise in [Ca²⁺]_i can result in the activation of apamin-sensitive SK channels and of the channels that underlie the sAHP. The activation of these channels may, however, depend on their location relative to NMDA receptors as well as on the spatial Ca²⁺ buffering within individual neurons.