Ca2+-independent secretory mechanism of thyrotropin-releasing hormone (TRH) involves protein kinase C in rat pituitary cells

doi:10.1016/S0006-291X(05)80073-7

Biochemical and Biophysical Research Communications

Volume 173, Issue 2, 14 December 1990, Pages 571-577

https://doi.org/10.1016/S0006-291X(05)80073-7 Get rights and content

Abstract

Thyrotropin-releasing hormone (TRH) stimulates biphasic prolactin (PRL) secretion from rat pituitary GH₃ cells. The pretreatment of cells with EGTA (100 μM) plus arachidonic acid (15 μM), a condition which decreased TRH-responsive intracellular Ca²⁺ pools, eliminated the activity of TRH on burst PRL secretion (2 min) but did not alter that on sustained PRL secretion (30 min). However, the treatment of cells with EGTA, arachidonic acid and H-7 (300 μM), a potent inhibitor of protein kinase C (PKC), almost completely suppressed the activity of TRH for sustained PRL secretion. In cells down-modulated for PKC, TRH abolished this Ca²⁺-independent sustained PRL secretion. These results suggest that TRH acts through a separate, Ca²⁺-independent secretory mechanism, besides by modulating the Ca²⁺-dependent mechanism and that PKC is involved in this Ca²⁺-independent secretory pathway.

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Cited by (9)

Thyrotropin-releasing hormone facilitates spinal nociceptive responses by potentiating NMDA receptor-mediated transmission
1996, European Journal of Pharmacology
The interaction of thyrotropin-releasing hormone (TRH) with NMDA receptor-mediated responses has been investigated in α-chloralose-anaesthetized spinalized rats with respect to its relevance to spinal nociceptive transmission. The effects of TRH and of the uncompetitive NMDA antagonist ketamine were tested on responses of dorsal horn wide dynamic range neurones to noxious pinch, heat and electrical stimuli in parallel with those to iontophoretically applied N-methyl-d-aspartate (NMDA) and AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid). Tests with NMDA blocking doses of ketamine (4 mg/kg i.v.) demonstrated a variable NMDA receptor-mediated component of all synaptic responses. TRH (0.5–1 mg/kg i.v.) enhanced the responses to NMDA (but not AMPA) in parallel with an increase of responses to all noxious stimuli and the ‘wind-up’ component of the responses to repeated electrical stimulation. This potentiation was completely reversed by a subsequent administration of ketamine (4 mg/kg i.v.). The results indicate that TRH facilitates nociceptive transmission in the spinal dorsal horn via a selective positive modulation of NMDA receptor-mediated transmission.
The role of the calpain-calpastatin system in thyrotropin-releasing hormone-induced selective down-regulation of a protein kinase C isozyme, nPKCε, in rat pituitary GH<inf>4</inf>C<inf>1</inf> cells
1995, Journal of Biological Chemistry
We have examined the mechanism for the selective down-regulation of protein kinase C ε (nPKCε) in rat pituitary GH₄C₁ cells responding to thyrotropin-releasing hormone (TRH) stimulation. Among various low molecular weight protease inhibitors examined, only a cysteine protease inhibitor (calpain inhibitor I, N-acetyl-Leu-Leu-norleucinal) blocked the down-regulation of nPKCε. Furthermore, the introduction of a synthetic calpastatin peptide, an exclusively specific inhibitor of calpain, into the cells also reduced the down-regulation, suggesting the involvement of calpain among all the intracellular cysteine proteases in this process. In accordance, we observed TRH-induced translocation of m-calpain from the cytosol to the membrane and the concomitant up-regulation of calpastatin isoforms; presumably, the former represents activation of the protease initiating the kinase degradation, while the latter constitutes a negative feedback system protecting the cells from activated calpain. These results suggest that in GH₄C₁ cells, TRH mobilizes both protease (m-calpain) and inhibitor (calpastatin) as a strictly regulating system for the nPKCε pathway mediating TRH signals.
Expression and signal transduction pathways of gonadotropin-releasing hormone receptors
1995, Recent Progress in Hormone Research
Gonadotropin-releasing hormone (GnRH)—the primary regulator of mammalian reproductive function—is produced in hypothalamic neurons and secreted episodically into the hypothalamic portal system of the median eminence. The distinctive distributions of GnRH-producing cells in the brain reflect their specific functions because GnRH acts as a neurohormone, neurotransmitter, or neuromodulator. In mammals, the majority of the GnRH neurons are located in the hypothalamus and are functionally coupled to form a pulse generator that determines the frequency of pulsatile GnRH release. This chapter discusses the major physiological action of GnRH, which is related to the control of gonadotropin secretion and is expressed through activation of GnRH receptors (GnRH-R) in the plasma membrane of pituitary gonadotrophs. Activation of GnRH receptors during agonist stimulation initiates a series of steps that lead to a cascade of intracellular responses. The first step is G protein-mediated activation of phospholipase C, leading to hydrolysis of phosphoinositides and the formation of InsP₃ and DAG. These initial changes determine the second step in signalling. The signal molecules of the phospholipase C-dependent pathway also exert positive and negative controls on the signal transduction mechanism, including the activities of phospholipase D and A₂ . These feedback mechanisms provide an additional degree of complexity in signaling that is important in the amplification, maintenance, and termination of specific aspects of the cellular activation pathways.
Thyrotropin-releasing hormone enhances excitatory postsynaptic potentials in neocortical neurons of the rat in vitro
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Several lines of evidence suggest a modulatory effect of thyrotropin-releasing hormone (TRH) on synaptic transmission in the mammalian neocortex. In the present study, the effects of this tripeptide on intracellularly recorded neocortical pyramidal neurons were investigated using rat in vitro brain slice preparations. TRH (5 μM and 50 μM) added to the perfusion medium concentration-dependently increased the excitability of pyramidal neurons, reflected by the number of spikes evoked by a depolarizing current pulse and by the augmentation of the time integral of glutamatergic excitatory postsynaptic potentials (EPSPs). TRH increased preferentially the time integrals of the late components of EPSPs (1-EPSPs) and increased their voltage-dependence. The early components of the EPSPs (e-EPSPs) were changed to much lesser extent. Iontophoretically applied d-2-amino-5-phosphonovalerate (d-APV) antagonized the TRH-induced increase of the 1-EPSPs. TRH also markedly enhanced the depolarizing responses evoked by iontophoretically applied $N- methyl- d -aspartate$ (NMDA), while the depolarizing responses evoked by (R,S)-α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and l-glutamate were not significantly affected. The depolarizing inward rectification present in all neurons studied was augmented by the higher concentration of TRH. The effects of TRH were incited after about 5 min and were long-lasting. In most neurons the effects of TRH on neuronal excitability did not completely recover during the 45 min washout period. The present data suggest that some of the non-hormonal actions of TRH in the neocortex may be due to an enhancement of glutamatergic synaptic transmission. The preferential enhancement of the NMDA receptor-mediated effects suggests a postsynaptic site of action of TRH.
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2002, Journal of Cellular Biochemistry
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2001, Naunyn-Schmiedeberg's Archives of Pharmacology

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^*: Supported in part by a research grant from the Foundation for Growth Science in Japan.

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Ca2+-independent secretory mechanism of thyrotropin-releasing hormone (TRH) involves protein kinase C in rat pituitary cells*

Abstract

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Ca²⁺-independent secretory mechanism of thyrotropin-releasing hormone (TRH) involves protein kinase C in rat pituitary cells*