Interaction of phencyclidine with voltage-dependent potassium channels in cultured rat hippocampal neurons: comparison with block of the NMDA receptor-ionophore complex

摘要: Whole-cell voltage-clamp recording techniques were used to investigate the blockade of voltage-dependent K+ channels by phencyclidine (PCP) in cultured rat hippocampal neurons. All recordings carried out presence tetrodotoxin (1-2 microM) eliminate Na+ currents. Step depolarization from a holding potential -40 mV activated slowly rising, minimally inactivating current (IK). PCP (0.5-1000 caused reduction maximum conductance IK [IC50(+30 mV), 22 microM] without altering its voltage dependency. The block diminished at depolarized potentials. Analysis according scheme Woodhull (1973) suggested that occurs via binding an acceptor site (presumably within channel pore) senses 40-50% transmembrane electrostatic field. had no effect on kinetic properties and failed show use dependency, suggesting may bind hydrophobic mechanism not requiring open channels. For comparison, we also investigated transient current, IA, step following 200 msec prepulse -90 (20 mM tetraethylammonium was present bathing solution reduce IK). In contrast potent blocking action IK, drug only affected IA high concentrations 224 microM]. At causing substantial (300-500 microM), produced acceleration inactivation rate, and, for brief (5-6 msec) depolarizing steps, suppression dependent. These observations suggest requires reduced inward responses induced excitatory amino acid agonist N-methyl-D-aspartate (NMDA) substantially lower than those required effects [IC50(-60 0.45 PCP-like dioxadrol stereoisomer dexoxadrol (10 blocked NMDA-evoked responses, while behaviorally inactive enantiomer levoxadrol did not. Dexoxadrol stereoselective fashion (IC50's, 73 260 microM, respectively), whereas sigma ligands (+)- (-)-SKF 10,047 (+)-3-[3-hydroxyphenyl]-N-(1-propyl)piperidine [(+)-3-PPP] little greater 300-500 microM). We conclude causes selective, neurons PCP- sigma-type site.(ABSTRACT TRUNCATED AT 400 WORDS)