Somatostatin increases a voltage-insensitive K+ conductance in rat CA1 hippocampal neurons

Somatostatin (SST) is a neuropeptide involved in several central processes. In hippocampus, SST hyperpolarizes CA1 pyramidal neurons and augments the K+ M current (I-M). However, the Limited involvement of I-M at resting potential in these cells suggests that the peptide also may modulate another channel to hyperpolarize hippocampal pyramidal neurons (HPNs). We studied the effect of SST on noninactivating conductances of rat CA1 HPNs in a slice preparation. Using MK886, a specific inhibitor of the enzymatic pathway that leads to the augmentation of I-M by SST, we have uncovered and characterized a second conductance activated by the peptide. SST did not affect I-M when applied with MK886 or the amplitudes of the slow Ca2+-dependent K+ afterhyperpolarization-current and the cationic Q current but still caused an outward current, indicating that SST acts upon another conductance. In the presence of MK886, SST elicited an outward current that reversed around -100 mV and that displayed a linear current-voltage relationship. Reversal potentials obtained in different external K+ concentrations are consistent with a conductance carried solely by K+ ions. The slope of the current-voltage relationship increased proportionately with the extracellular K+ concentration and remained linear. This suggests that SST opens a voltage-insensitive leak current (I-K(L)) in HPNs not an inwardly rectifying K+ current as reported in other neuron types. A low concentration of extracellular Ba2+ (150 mu M) only slightly decreased the SST-induced effect in a voltage-independent manner, whereas a high concentration of Ba2+ (2 mM) completely blocked it. Extracellular Cs+ (2 mM) did not affect the outward SST current but inhibited the inward component. We conclude that SST inhibits HPNs by activating two different K+ conductances: the voltage-insensitive I-K(L) and the voltage-dependent I-M. The hyperpolarizing effect of SST at resting membrane potential appears to be mainly carried by I-K(L), whereas I-M dominates at slightly depolarized potentials.