Analysis of nociceptin-induced spontaneous transient outward currents and their physiological function in the CNS

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Spontaneous transient outward currents (STOCs) have been found in peripheral neurons and smooth muscle cells, but rarely in central neurons. Using a nystatin-perforated patch clamp technique, we succeeded in recording STOCs in mouse dentate gyrus granule cells. Nociceptin increased the amplitude and frequency of STOCs. We consider modulation of STOCs to be a new means to regulate cell activity in central neurons, and studied their characteristics and mechanism of augmentation. The whole-cell current-voltage relationship showed outward rectification and the reversal potential was close to the equilibrium potential for K The frequency of STOCs increased at depolarized potentials. Tetraethylammonium, iberiotoxin and a Ca^<2+> chelator BAPTA-AM inhibited STOCs. These results suggest the involvement of large-conductance Ca^<2+>-activated K^+ channels. Single-channel recordings in the inside-out configuration revealed Ca^<2+>-activated K^+ channels with a conductance ranging from 82 to 352 p … More S. The augmenting effect of nociceptin was cancelled by [Phe^1Ψ(CH -NH)Gly^2]Nociceptin(1-13)NH. Cd^<2+> did not affect the transient outward currents or augmentation by nociceptin. Whereas nociceptin, theophylline and cyclic ADP ribose induced transient outward currents with short duration observed under control conditions, inositol 1, 4, 5-trisphosphate induced transient outward currents with long duration, in addition to those with short duration. Ryanodine inhibited nociceptin from augmenting STOCs. Our data suggest that Ca^<2+> sparks, not Ca^<2+> quarks, transiently activate large-conductance Ca -activated K^+ channels to induce transient outward currents Nociceptin probably sensitizes ryanodine receptors and increases transient outward currents to reduce cell excitability. Nociceptin-induced increase in the amplitude and frequency of STOCs was observed even in the nociceptin receptor knockout mice, suggesting the presence of receptor subtype. In this study, we first revealed the presence and the characteristics of STOCs in the CNS and the modulation of STOCs by G protein coupled receptor. Less