Characteristics of thyrotropin releasing hormone (TRH) receptors in rat brain

Ogawa, Norio; Yamawaki, Yasuhide; Kuroda, Hiroo; Nukina, Itaru; Ota, Zensuke; Fujino, Masahiko; Yanaihara, Noboru

doi:10.1016/0196-9781(82)90169-3

Cited by 73 publications

(16 citation statements)

References 29 publications

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“…Also, autoradiographic studies have revealed that TRH receptors of the brain are concentrated in the cerebral cortex and the limbic system (2,3). Based on these findings, TRH is considered to play an important role in the brain in the maintenance of consciousness and emotional or intellectual functions (4). Moreover, Yarbrough and Pomara (5) recommended the use of TRH for the treatment of dementia of the Alzheimer type (DAT) from the functional relationship between TRH and central cholinergic nervous system and the effectiveness of TRH in the treatment of dementia of patients with amyotrophic lateral sclerosis complicated by degeneration of cholinergic nerves, and by Metcalf (6) and Griffiths (7) from the effect of TRH to improve disturbance of consciousness (8) and its antidepressant effect (9,10).…”

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confidence: 99%

Pharmacological study of TA-0910, a new thyrotropin-releasing hormone(TRH) analog. (IV). Effects on experimental memory impairment in mice and rats.

Yamamura¹,

Kawakami²,

Nakagawa³

et al. 1991

Jpn.J.Pharmacol

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ABSTRACT-The effects of a new TRH analog, TA-0910, orally administered, on experimental memory impairments for the one-trial passive avoidance response in anoxic mice (light-dark box), active avoidance response in basal forebrain (BF)-lesioned rats (shuttle box), and delayed alternation task in scopolamine-treated rats (T-maze) were studied. In mice, TA-0910 (3 -30 mg) administered 60 min before the retention trial dose-dependently prolonged the passive avoidance response latency reduced by C02-exposure that was given immediately after the acquisition trial, but not when it was given 60 min before the acquisition or just after the anoxic treatment. In rats, TA-0910 (0.3-3 mg/kg) administered 40-60 min before the test trial, dose-dependently prevented the reduction in mean avoidance rate caused by BF-lesioning and elevated the scopolamine (0.1 mg/kg, i.p.)-induced reduction in percent correct choice level in the alternation task. TRH (30 -300 mg/kg), on the other hand, produced no improvements in any of the above tests. These results suggest that TA-0910 improves impaired memory by correcting the retrieval process of memory.Thyrotropin-releasing hormone (TRH) is a hypothalamic hormone that stimulates secretion of thyrotropin and prolactin. However, radioimmunoassay has demonstrated that twothirds of the total TRH content of the brain is distributed widely in areas other than the hypothalamus (1). Also, autoradiographic studies have revealed that TRH receptors of the brain are concentrated in the cerebral cortex and the limbic system (2, 3). Based on these findings, TRH is considered to play an important role in the brain in the maintenance of consciousness and emotional or intellectual functions (4). Moreover, Yarbrough and Pomara (5) recommended the use of TRH for the treatment of dementia of the Alzheimer type (DAT) from the functional relationship between TRH and central cholinergic nervous system and the effectiveness of TRH in the treatment of dementia of patients with amyotrophic lateral sclerosis complicated by degeneration of cholinergic nerves, and by Metcalf (6) and Griffiths (7) from the effect of TRH to improve disturbance of consciousness (8) and its antidepressant effect (9, 10).Recently, improvements in mental symptoms (such as disturbances in impressibility, emotional disturbances, reduced ability to think, deduced spontaneity, inertia, and apathy) were reported in patients with Alzheimer's disease (AD) and cerebrovascular dementia after administration of TRH (11,12). Tem-

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confidence: 99%

Pharmacological study of TA-0910, a new thyrotropin-releasing hormone(TRH) analog. (IV). Effects on experimental memory impairment in mice and rats.

Yamamura¹,

Kawakami²,

Nakagawa³

et al. 1991

Jpn.J.Pharmacol

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“…In previous studies, binding of TRH has been found to decrease under disulfide bond reducing conditions (18,19). The studies presented here were undertaken to determine whether the conserved Cys at position 98 (Cys-98) of EC-1 and the conserved Cys-179 of EC-2 of TRH-R are covalently linked by a disulfide bond and whether this linkage is necessary for normal TRH-R function.…”

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confidence: 99%

A Disulfide Bond between Conserved Extracellular Cysteines in the Thyrotropin-releasing Hormone Receptor Is Critical for Binding

Perlman

Wang

Nussenzveig

et al. 1995

Journal of Biological Chemistry

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The assumption that a disulfide bond is present between two highly conserved cysteines in the extracellular loops of G protein-coupled receptors and is critical for receptor function has been cast in doubt. We undertook to determine whether a disulfide bond important for binding or activation is present in the thyrotropinreleasing hormone (TRH) receptor (TRH-R). Studies were performed with cells expressing wild-type (WT) and mutant receptors in the absence or presence of the reducing agent dithiothreitol (DTT). The affinity of WT TRH-R was 16 -22-fold lower in the presence of DTT than in the absence of DTT. Mutant receptors were constructed in which Ala was substituted for conserved Cys-98 and Cys-179 of extracellular loops 1 and 2, respectively, and for the nonconserved Cys-100. C98A and C179A TRH-Rs did not exhibit high affinity binding. These mutant receptors were capable of stimulating inositol phosphate second messenger formation to the same extent as WT TRH-Rs but with a markedly lower potency. The affinities of C98A and C179A TRH-Rs, estimated from their potencies, were 4400-and 640-fold lower, respectively, than WT TRH-R. The estimated affinities of neither C98A nor C179A TRH-R were decreased by DTT. In contrast, the estimated affinity of C100A TRH-R was not different from WT TRH-R and was DTT sensitive. Moreover, the effect of mutating both Cys-98 and Cys-179 was not additive with the effects of the individual mutations. These data provide strong evidence that Cys-98 and Cys-179 form a disulfide bond. This interaction is not involved in receptor activation but is critical for maintaining the high affinity conformation of TRH-R.

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“…The highest specific binding of (3H)TRH occurs in synaptic membrane fractions of rat brain (Ogawa et al 1982). These findings suggest that TRH is a neurotransmitter or a neuromodulator, because synaptosomes are particularly rich in TRH (Barnea et al 1975;Warberg et al 1977).…”

Section: Discussionmentioning

confidence: 84%

“…The receptor preparation and standard TRH radioreceptor assays (RRA) were carried out according to the procedures described in earlier papers (Ogawa et al 1981;Ogawa et al 1982 …”

Section: Methodsmentioning

confidence: 99%