TXA₂ agonists inhibit high-voltage-activated calcium channels in rat hippocampal CA1 neurons

Whole cell voltage clamp recordings were used to investigate the effects of thromboxane A₂ (TXA₂) agonists on the voltage-dependent Ca²⁺ currents in rat hippocampal CA1 neurons. TXA₂ agonists, |1S-|1α, 2β(5Z), 3α(1E, 3S*)4α]|-7-|3-|3-hydroxy-4-(4'-iodophenoxy)-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 TXA₂ receptor antagonist, SQ-29548. I-BOP as well as U-46619 inhibited both ω-conotoxin GVIA (CgTx)-sensitive and nimodipine-sensitive Ca²⁺ currents but had no effect on CgTx/nimodipine-insensitive Ca²⁺ currents. The I-BOP and U-46619 inhibition of Ca²⁺ currents was blocked by internal dialysis of hippocampal neurons with specific protein kinase C (PKC) inhibitors, NPC-15437 and PKC inhibitor-(19-36). Pretreatment of hippocampal neurons with either 5 μg/ml pertussis toxin (PTX) or 5 μg/ml cholera toxin (CTX) did not significantly affect the suppression of the Ca²⁺ currents by I-BOP and U-46619. Dialyzing with 1 mM guanosine 5'-O-(3-thiotriphosphate) or 1 mM GDP significantly attenuated the I-BOP or U-46619 action. These results demonstrate that TXA₂ agonists inhibit both CgTx- and nimodipine-sensitive Ca²⁺ currents but not CgTx/nimodipine-insensitive currents in rat hippocampal CA1 neurons via a PTX- and CTX-insensitive G protein-coupled activation of the PKC pathway.