TXA(2) AGONISTS INHIBIT HIGH-VOLTAGE-ACTIVATED CALCIUM CHANNELS IN RAT HIPPOCAMPAL CA1 NEURONS

Whole cell voltage clamp recordings were used to investigate the effec ts of thromboxane A(2) (TXA(2)) agonists on the voltage-dependent Ca2 currents in rat hippocampal CAl neurons. TXA(2) agonists, {1S-[1 alph a, 2 beta(5Z), 3 alpha(1E, 3S)4 ha]}-7-[3-[3-hydroxy-4-(4'-iodophenox y)-1-butenyl] -7-oxabicyclo[2,2,1]heptan-2-yl]-5-heptenoic acid (I-BOP ) and U-46619, reversibly suppressed the whole cell Ca2+ currents in a concentration-dependent manner. The effect was blocked by specific TX A(2) receptor antagonist, SQ-29548. I-BOP as well as U-46619 inhibited both omega-conotoxin GVIA (CgTx)-sensitive and nimodipine-sensitive C a2+ currents but had no effect on CgTx/nimodipine-insensitive Ca2+ cur rents. The I-BOP and U-46619 inhibition of Ca2+ currents was blocked b y internal dialysis of hippocampal neurons with specific protein kinas e C (PKC) inhibitors, NPC-15437 and PKC inhibitor-(19-36). Pretreatmen t of hippocampal neurons with either 5 mu g/ml pertussis toxin (PTX) o r 5 mu g/ml cholera toxin (CTX) did not significantly affect the suppr ession of the Ca2+ currents by I-BOP and U-46619. Dialyzing with 1 mM guanosine 5'-O-(3-thiotriphosphate) or 1 mM GDP significantly attenuat ed the I-BOP or U-46619 action. These results demonstrate that TXA(2) agonists inhibit both CgTx- and nimodipine-sensitive Ca2+ currents but not CgTx/nimodipine-insensitive currents in rat hippocampal CA1 neuro ns via a PTX- and CTX-insensitive G protein-coupled activation of the PKC pathway.