MODULATION OF VOLTAGE-GATED CALCIUM CHANNELS BY ORPHANIN FQ IN FRESHLY DISSOCIATED HIPPOCAMPAL-NEURONS

Orphanin FQ (OFQ) has recently been reported to be an endogenous ligan d for the opioid-like LC132 receptor. The effect of OFQ on high voltag e-gated calcium channels (VGCCs) was examined in freshly dissociated r at pyramidal neurons using the whole-cell configuration of the patch-c lamp technique. High-threshold Ba2+ currents were reversibly inhibited by OFQ. The depression of the currents was associated with a slowed r ate of activation and a change in the activation I-V relationship at s tep potentials higher than +30 mV. In concentration-response ex perime nts, a mean (+/-SEM) pEC(50) value of 7.0 +/- 0.07 and a Hill coeffici ent of 1.5 +/- 0.08 (n = 5) were obtained. The near maximum inhibition of the Ba2+ currents by OFQ (1 mu M) amounted to 31 +/- 2.2% of contr ol (n = 15). Opioid receptors could not account for the effects of OFQ on VGCCs, because naloxone, a broad spectrum mu-, delta-, and kappa-r eceptor antagonist, did not reduce the effectiveness of OFQ. When GTP- gamma-S was included in the pipette, the depression of the currents by OFQ was irreversible, whereas currents from neurons preincubated with pertussis toxin were not inhibited by OFQ, consistent with the involv ement of a PTX-sensitive G-protein. When selective blockers of VGCCs w ere used, it was demonstrated that all subtypes of VGCCs were affected by OFQ. In conclusion, the effect of OFQ on VGCCs expressed in hippoc ampal CA3 and CA1 neurons may play an important role in the regulation of hippocampal cell excitability and neurotransmitter release.