Role of TRH receptors as possible mediators of analeptic actions of TRH-like peptides

Hinkle, Patricia M.; Pekary, A. Eugene; Senanayaki, Shayani; Sattin, Albert

doi:10.1016/s0006-8993(02)02454-x

Cited by 43 publications

(30 citation statements)

References 16 publications

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“…Hinkle (Hinkle et al, 2002) studied the pharmacology of several TRH analogs, in which the His at position-2 was replaced by other amino acids, and found there was no correlation between the analeptic activities and the binding and signaling potencies of these analogs at TRH-R1 or TRH-R2. Hogan (Hogan et al, 2008) reported that a pentapeptide analog of TRH (pGlu-Asn-Pro-D-Tyr-D-TRPNH 2 ) competed with [ 3 H]MeTRH for binding to sites in the hippocampus and cortex, but did not bind to TRH-R1 or TRH-R2.…”

Section: Discussionmentioning

confidence: 99%

Thyrotropin-Releasing Hormone Receptor Type 1 (TRH-R1), not TRH-R2, Primarily Mediates Taltirelin Actions in the CNS of Mice

Thirunarayanan

Nir

Raaka

et al. 2012

Neuropsychopharmacol

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Thyrotropin-releasing hormone receptor type 2 (TRH-R2), not TRH-R1, has been proposed to mediate the CNS effects of TRH and its more effective analog taltirelin (TAL). Consistent with this idea, TAL exhibited higher binding affinity and signaling potency at mouse TRH-R2 than TRH-R1 in a model cell system. We used TRH-R1 knockout (R1ko), R2ko and R1/R2ko mice to determine which receptor mediates the CNS effects of TAL. There was no TRH-R1 mRNA in R1ko and R1/R2ko mice and no TRH-R2 mRNA in R2ko and R1/R2ko mice. Specific [ 3 H]MeTRH binding to whole brain membranes was 5% of wild type (WT) for R1ko mice, 100% for R2ko mice and 0% for R1/R2ko mice, indicating TRH-R1 is the predominant receptor expressed in the brain. In arousal assays, TAL shortened sleep time with pentobarbital sedation in WT and R2ko mice by 44 and 49% and with ketamine/xylazine sedation by 66 and 55%, but had no effect in R1ko and R1/R2ko mice. In a tail flick assay of nociception, TAL increased response latency by 65 and 70% in WT and R2ko mice, but had no effect in R1ko and R1/R2ko mice. In a tail suspension test of depression-like behavior, TAL increased mobility time by 49 and 37% in WT and R2ko mice, but had no effect in R1ko and R1/R2ko mice. Thus, in contrast to the generally accepted view that the CNS effects of TAL are mediated by TRH-R2, these effects are mediated primarily if not exclusively by TRH-R1 in mice. Neuropsychopharmacology (2013) 38, 950-956;

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Section: Discussionmentioning

confidence: 99%

Thyrotropin-Releasing Hormone Receptor Type 1 (TRH-R1), not TRH-R2, Primarily Mediates Taltirelin Actions in the CNS of Mice

Thirunarayanan

Nir

Raaka

et al. 2012

Neuropsychopharmacol

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“…Indeed, intracerebroventricular administration of TRH dramatically reduces sleep time in rats (Hinkle et al, 2002). Furthermore, in canine narcolepsy, TRH analogs alleviate the hallmark symptoms of daytime sleepiness and cataplexy (Nishino et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Excitatory Effects of Thyrotropin-Releasing Hormone in the Thalamus

Broberger¹,

McCormick²

2005

J. Neurosci.

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The activity of the thalamus is state dependent. During slow-wave sleep, rhythmic burst firing is prominent, whereas during waking or rapid eye movement sleep, tonic, single-spike activity dominates. These state-dependent changes result from the actions of modulatory neurotransmitters. In the present study, we investigated the functional and cellular effects of the neuropeptide thyrotropin-releasing hormone (TRH) on the spontaneously active ferret geniculate slice. This peptide and its receptors are prominently expressed in the thalamic network, yet the role of thalamic TRH remains obscure. Bath application of TRH resulted in a transient cessation of both spindle waves and the epileptiform slow oscillation induced by application of bicuculline. With intracellular recordings, TRH application to the GABAergic neurons of the perigeniculate (PGN) or thalamocortical cells in the lateral geniculate nucleus resulted in depolarization and increased membrane resistance. In perigeniculate neurons, this effect reversed near the reversal potential for K ϩ , suggesting that it is mediated by a decrease in K ϩ conductance. In thalamocortical cells, the TRH-induced depolarization was of sufficient amplitude to block the generation of rebound Ca 2ϩ spikes, whereas the even larger direct depolarization of PGN neurons transformed these cells from the burst to tonic, single-spike mode of action potential generation. Furthermore, application of TRH prominently enhanced the afterdepolarization that follows rebound Ca 2ϩ spikes, suggesting that this transmitter may also enhance Ca 2ϩ -activated nonspecific currents. These data suggest a novel role for TRH in the brain as an intrinsic regulator of thalamocortical network activity and provide a potential mechanism for the wake-promoting and anti-epileptic effects of this peptide.

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“…Hinkle et al [50] tested a number of TRH-like peptides and determined that Val 2 -TRH and Leu 2 -TRH are analeptics following intracisternal injection while Phe 2 -TRH and Tyr 2 -TRH are not. This further indicated that the imidazole ring is not necessary for the analeptic activity and that a hydrophobic residue at position 2 is not sufficient.…”

Section: Histidinementioning

confidence: 99%

Thyrotropin-Releasing Hormone Analogs

Colson

Gershengorn²

2006

MRMC

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Thyrotropin releasing hormone (TRH: pyroglutamic acid-histidine-prolineamide) regulates the activity of cells in the anterior pituitary and within the central and peripheral nervous systems. TRH, which has been the subject of much research over the past three decades, exerts its effects by acting through class A G-protein coupled receptors. The recent discovery of a second receptor subtype has generated an interest in the discovery of receptor subtype-selective TRH analogs. In this review, we describe advances in the development of TRH analogs and in the understanding of their mechanism of interaction with TRH receptors. We also describe the recent breakthrough in the identification of analogs that bind selectively at TRH-R2.

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Role of TRH receptors as possible mediators of analeptic actions of TRH-like peptides

Cited by 43 publications

References 16 publications

Thyrotropin-Releasing Hormone Receptor Type 1 (TRH-R1), not TRH-R2, Primarily Mediates Taltirelin Actions in the CNS of Mice

Thyrotropin-Releasing Hormone Receptor Type 1 (TRH-R1), not TRH-R2, Primarily Mediates Taltirelin Actions in the CNS of Mice

Excitatory Effects of Thyrotropin-Releasing Hormone in the Thalamus

Thyrotropin-Releasing Hormone Analogs

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