Dual modulation of K+ currents and cytosolic Ca2+ by the peptide TRH and its derivatives in guinea-pig septal neurones

1. We describe a dual effect of the peptide TRH (thyrotrophin-releasing hormone) and its derivatives at concentrations between 0.1 and 1 microM on the K+ currents and cytosolic Ca2+ concentration in enzymatically dispersed septal neurones. 2. In response to membrane depolarization, septal neurones recorded under whole-cell patch clamp can generate two major K+ currents: (i) a fast and transient K+ current (I(t)), that after a maximum at 2-5 ms inactivates completely at all membrane potentials in less than 50 ms; and (ii) a slowly activating current (I(s)), which reaches a maximum in 15-20 ms and does not exhibit appreciable inactivation during short-lasting voltage pulses. 3. In about 70% of the neurones tested (n = 48) TRH induced a reversible, and often transient, increase of I(t), I(s) or both K+ conductaNces. In approximately 10% of the cells the peptide had an opposite effect and caused a more protracted and partially reversible attenuation of the amplitude of I(t) and I(s). 4. The dual action of TRH on the K+ currents was mimicked by its derivatives but the effects varied depending on their structural relationship with the precursor neuropeptide. The physiological metabolite cyclo-His-Pro and the synthetic analogue methyl-TRH, in which the carboxyl terminus of the molecule is conserved, increased the K+ currents, whereas depression of the K+ conductances was predominantly observed in the presence of TRH-OH, in which the amino end of TRH is maintained intact. 5. In fura-2-loaded unclamped cells, TRH induced either release of Ca2+ from internal stores, Ca2+ entry, or both. With TRH-OH we never observed mobilization of internal Ca2+ but this peptide evoked a large Ca2+ influx. 6. The results demonstrate that the physiological metabolites of brain TRH (cyclo-His-Pro and TRH-OH) have biological activity. TRH and its derivatives exert two types of regulatory actions on the voltage-gated K+ channels and cytosolic Ca2+ concentration in central neurones, which can be explained assuming that TRH and TRH-derived products interact with different subtypes of brain receptors recognizing preferentially either the amino or the carboxyl termini of the TRH molecule.