SOMATOSTATIN MODULATES HIGH-VOLTAGE-ACTIVATED CA2+ CHANNELS IN FRESHLY DISSOCIATED RAT HIPPOCAMPAL-NEURONS

1. The effects of somatostatin (SS) on the low-voltage-activated and high-voltage-activated (HVA) Ca2+ channels in pyramidal neurons acutely dissociated from the hippocampal CA1 region of 2- to 3-wk-old rats were investigated in a nystatin perforated-patch recording configuration under voltage-clamp conditions. 2. SS had no effect on the low-voltage-activated Ca2+ channel but did inhibit the HVA Ca2+ channel in a concentration-, time-, and voltage-dependent manner. 3. SS slowed the activation phase of Ba2+ current (I-Ba) passing through HVA Ca2+ channels, and the maximum inhibition was 28% of the total current amplitude measured 10 ms after the current activation. The inhibitory effect was eliminated by applying larger depolarizing prepulses. Pretreatment with pertussis toxin (PTX) completely blocked the effect of SS on HVA I-Ba, suggesting the contribution of PTX-sensitive G(i)/G(o) proteins to the SS-induced inhibition. 4. The applications of forskolin, 8-Br-cAMP, dibutyryl-guanosine 3'5'-cyclic monophosphate, staurosporine, and 1-(5-isoquinolinylsulphonyl)-2-methylpiperazine -2-methylpiperazine did not affect either the control HVA I-Ba or the SS-induced inhibition of HVA I-Ba. 5. Pretreatment with protein kinase C (PKC) activators had no significant effect on HVA I-Ba but did remove the inhibition of HVA I-Ba by SS. 6. omega-Conotoxin-GVIA, omega-agatoxin-IVA, nicardipine, and omega-conotoxin-MVIIC blocked HVA I-Ba by 27, 13, 38, and 9% of the total HVA current, respectively, which suggested the existence of N-, P-, L-, and Q-type HVA Ca2+ channels in the hippocampal CA1 pyramidal neurons. A current that was insensitive to these Ca2+ channel antagonists, termed an R-type HVA Ca2+ channel current, was also found to exist. This residual R-type Ca2+ channel was completely blocked by addition of 200 mu M Cd2+. 7. SS significantly inhibited only the N-type HVA Ca2+ channel, which is one of the five types of HVA Ca2+ channels. 8. The above results suggest that SS selectively inhibits the N-type HVA Ca2+ channel via the PTX-sensitive G(i)/G(o) protein in the hippocampal CA1 pyramidal neurons while the SS-induced inhibition is also regulated by the PKC-mediated pathway.