Phencyclidine block of calcium current in isolated guinea-pig hippocampal neurones.
J M Ffrench-Mullen, M A Rogawski
The Journal of Physiology October 1992 DOI: 10.1113/jphysiol.1992.sp019328 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro electrophysiology study (whole-cell voltage clamp) Peer reviewed |
|---|---|
| Population | Enzymatically dissociated CA1 hippocampal neurones from adult guinea-pigs, with comparison to rat dorsal root ganglion neurones |
| Interventions | Phencyclidine (PCP) tiletamine dizocilpine (MK-801) ketamine |
| Key points | PCP blocked hippocampal calcium channel current in a use-dependent, voltage-dependent manner with a steady-state IC50 of 7 microM, about 13 times more potent than at rat dorsal root ganglion neurones (IC50 90 microM). Blocking rates were at least 60 times faster at depolarized than resting voltages, and the blocking site appears to sense 56% of the transmembrane electric field. PCP increased apparent inactivation without affecting activation or deactivation, which the authors say indicates block does not occur by a conventional open-channel mechanism. |
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 10(6) 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 microM. 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 microM). 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 Ba(2+)-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 PCP indicating that the block does not occur by a conventional open channel mechanism.(ABSTRACT TRUNCATED AT 400 WORDS)