Phencyclidine block of calcium current in isolated guinea-pig hippocampal neurones

J. M H Ffrench-Mullen, Michael A Rogawski

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21 Scopus citations

Abstract

1. Phencyclidine (PCP) block of Ca2+ channel current in enzymatically dissociated neurones from the CA1 region of the adult guinea-pig hippocampus was studied using whole-cell voltage clamp techniques. Ca2+ channel current was recorded with 3 mM- Ba2+ as the charge carrier. Na+ currents were blocked with tetrodotoxin and K+ currents were eliminated by using tetraethylammonium and N-methyl-D-glucamine as the predominant extracellular and intracellular cations, respectively. 2. Peak Ca2+ channel current evoked by depolarization from -80 to -10 mV was reduced in a use-dependent fashion by PCP. The apparent forward and reverse rate constants for block at the depolarized voltage were 106 S-1 M-1 and 11-14 S-1, respectively. These values were at least 60 times faster than the corresponding rates at the resting voltage. The steady-state block produced by PCP increased in a concentration-dependent fashion with an IC50 of 7 μM. Other dissociative anaesthetic drugs were substantially weaker inhibitors of the current (tiletamine > dizocilpine (MK-801) > ketamine). 3. The Ca2+ channel current recorded under identical conditions in rat dorsal root ganglion neurones was less sensitive to blockade by PCP (IC50, 90 μM). 4. PCP block of the hippocampal Ca2+ channel current occurred in a voltage dependent fashion with the fractional block decreasing at positive membrane potentials. Analysis indicated that the PCP blocking site senses 56% of the transmembrane electric field. 5. Analysis of tail currents recorded at -80 mV demonstrated that PCP does not affect the voltage-dependent or time-dependent activation or deactivation of the Ca2+ channel current. 6. The rate and extent of inactivation of the Ca2+ channel current was maximal at -10 mV and diminished at more positive potentials. Experiments with Ba2+ -free external solution demonstrated that inactivation of the Ca2+ channels is largely voltage-dependent and is not affected by Ba2+ influx. 7. PCP markedly increased the apparent extent of inactivation of the Ca2+ channel current during prolonged voltage steps. This increase in apparent inactivation was more pronounced at depolarized potentials. Inactivation at -10 mV proceeded in two exponential phases; PCP had little effect on the fast decay phase and caused a moderate speeding of the slow decay phase. Although block of the activated state evolved on the same time scale as inactivation, the apparent rate of inactivation was not increased in a concentration-dependent fashion by PC indicating that the block does not occur by a conventional open channel mechanism. 8. We conclude that the potent blocking action of PCP on Ca2+ channel current in CA1 hippocampal neurones occurs by binding of the drug to an activated state of the Ca2+ channel that is distinct from the open state. This use-dependent blockade of Ca2+ channels may account for certain of PCPs unique behavioural actions, particularly those not shared by ketamine and dizocilpine which are only weak Ca2+ channel antagonists.

Original languageEnglish (US)
Pages (from-to)85-105
Number of pages21
JournalJournal of Physiology
Volume456
StatePublished - 1992
Externally publishedYes

ASJC Scopus subject areas

  • Physiology

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