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Dual modulation of K+ currents and cytosolic Ca2+ by the peptide TRH and its derivatives in guinea‐pig septal neurones.
Author(s) -
ToledoAral J,
Castellano A,
Ureña J,
LópezBarneo J
Publication year - 1993
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.1993.sp019949
Subject(s) - guinea pig , cytosol , peptide , chemistry , dual (grammatical number) , biophysics , medicine , endocrinology , biochemistry , biology , philosophy , enzyme , linguistics
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.