Thyrotropin-releasing hormone stimulates GTP hydrolysis by membranes from GH4C1 rat pituitary tumor cells.

Hinkle, Patricia M.; Phillips, William J.

doi:10.1073/pnas.81.19.6183

Cited by 61 publications

(7 citation statements)

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“…Initially characterized in clonal rat pituitary cell lines, TRH binding sites were later identified in brain membranes (Hinkle and Tashjian, 1973; Burt and Snyder, 1975). The link between TRH receptors and G proteins was made at a time when heterotrimeric G proteins were thought to transduce signals only from receptors coupled to adenylyl cyclase (Hinkle and Kinsella, 1984; Hinkle and Phillips, 1984). It quickly became clear that TRH receptors belong to the G protein-coupled receptor (GPCR) superfamily.…”

Section: Introductionmentioning

confidence: 99%

Desensitization, Trafficking, and Resensitization of the Pituitary Thyrotropin-Releasing Hormone Receptor

Hinkle¹,

Gehret²,

Jones³

2012

Front. Neurosci.

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The pituitary receptor for thyrotropin-releasing hormone (TRH) is a calcium-mobilizing G protein-coupled receptor (GPCR) that signals through Gq/11, elevating calcium, and activating protein kinase C. TRH receptor signaling is quickly desensitized as a consequence of receptor phosphorylation, arrestin binding, and internalization. Following activation, TRH receptors are phosphorylated at multiple Ser/Thr residues in the cytoplasmic tail. Phosphorylation catalyzed by GPCR kinase 2 (GRK2) takes place rapidly, reaching a maximum within seconds. Arrestins bind to two phosphorylated regions, but only arrestin bound to the proximal region causes desensitization and internalization. Phosphorylation at Thr365 is critical for these responses. TRH receptors internalize in clathrin-coated vesicles with bound arrestin. Following endocytosis, vesicles containing phosphorylated TRH receptors soon merge with rab5-positive vesicles. Over approximately 20 min these form larger endosomes rich in rab4 and rab5, early sorting endosomes. After TRH is removed from the medium, dephosphorylated receptors start to accumulate in rab4-positive, rab5-negative recycling endosomes. The mechanisms responsible for sorting dephosphorylated receptors to recycling endosomes are unknown. TRH receptors from internal pools help repopulate the plasma membrane. Dephosphorylation of TRH receptors begins when TRH is removed from the medium regardless of receptor localization, although dephosphorylation is fastest when the receptor is on the plasma membrane. Protein phosphatase 1 is involved in dephosphorylation but the details of how the enzyme is targeted to the receptor remain obscure. It is likely that future studies will identify biased ligands for the TRH receptor, novel arrestin-dependent signaling pathways, mechanisms responsible for targeting kinases and phosphatases to the receptor, and principles governing receptor trafficking.

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Section: Introductionmentioning

confidence: 99%

Desensitization, Trafficking, and Resensitization of the Pituitary Thyrotropin-Releasing Hormone Receptor

Hinkle¹,

Gehret²,

Jones³

2012

Front. Neurosci.

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“…Hence, these findings support the hypothesis that phospholipase C-mediated hydrolysis of PtdIns(4,5)P 2 induced by TRH is not a consequence of an elevation of [ Ca2 +] i, but rather may be an early event in the sequence leading to an elevation of [ C a2+]i. The molecular details of the mechanism by which the TRH -receptor complex may be coupled to the phospholipase C enzyme are not known; however, there is some evidence that a guanine nucleotide binding protein may be involved (35,36).…”

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confidence: 99%

Mechanism of Thyrotropin Releasing Hormone Stimulation of Pituitary Hormone Secretion

Gershengorn¹

1986

Annu. Rev. Physiol.

311

120

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INTRODUCTIONDuring the past several years, the mechanism of action of thyrotropin-releasing hormone (TRH; thyroliberin) has been studied intensively in GH cells, cloned rat mammotropic tumor cell lines that appear to be valid models for in vitro study of mammotroph fu nction (30,34,48). In this article I review the recent findings (see 26 for previous review) that fo rm the basis for a detailed hypoth esis to explain the transduction of the TRH signal at the cell surface into stimulation of prolactin secretion.It is generally agreed that an elevation of cyt9plasmic free calcium ion concentration ([Ca2+]i) serves to couple, at least in part, the binding of many hormones and neurotransmitters to plasma membrane receptors with the stimulation of a variety of cellular processes (51). The elevation of [ Ca2+]i induced by these stimulants may be caused by mobilization (or redistribution) of intracellular calcium, or by enhancement of influx of extracellular Ca2+ , or both (17). It has been demonstrated that in some of these cells a very rapid effect after stimulant-receptor interaction is enhanced hydrolysis of phosphatidylin ositoI4,5-bisphosphate [PtdIns( 4,5)P 2 ] by a phospholipase C (or phosphodies terase) to yield 1 ,2 -diacylglycerol (DG) and inositoltrisphosphate (InsP3) (18). Furthermore, it has been proposed that both DG (50) and InsP3 (11) may serve as intracellular mediators (or second messengers) to transduce and amplify the signal, leading to stimulation of the physiologic response(s). DG appears to 515 0066-4278/86/0315-0515$02.00Annu. Rev. Physiol. 1986.48:515-526. Downloaded from www.annualreviews.org Access provided by University of California -Davis on 02/04/15. For personal use only. Quick links to online content Further ANNUAL REVIEWS 516 GERSHENGORN exert its effects by enhancing the activity of a Ca 2 + -and phospholipid dependent protein kinase (protein kinase C) by an action that does not depend on an elevation of [Ca2+];. InsP3 appears to act to mobilize calcium from an intracellular pool to elevate [Ca2+]i' In addition, influx of extracellular calcium may be enhanced by hormones and neurotransmitters to elevate [Ca2+]i' The elevation of [Ca2+]; may activate a Ca2+ -and calmodulin-dependent protein kinase(s) and, perhaps, other processes. It appears that this generalized schema of signal transduction by separate but converging pathways involving Ca2+ �nd lipid messengers may describe the mechanism of TRH stimulation of prolactin secretion. TRH AND PHOSPHOINOSITIDESIn this section I present evidence that strongly supports the concept that in GH cells TRH acts to stimulate the hydrolysis of Ptdlns(4,5)P 2 by a phospholipase C to yield InsP 3 and DG, and that this action may be the initial step in the sequence of intracellular events leading to prolactin secretion. The studies I emphasize have been performed in cells prelabeled with precursors to isotopic equilibrium in order to facilitate measurement of changes in the cellular content of even minor substances, such as PtdIns(4, 5)P2 and InsP3. ...

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“…8,[20][21][22][23] On the other hand, we have previously reported that the presence or absence of TRH-induced paradoxical GH secretion reflects the clinical and biological profiles of GH-secreting adenomas. 7 Prior studies have identified that the TRH receptor belongs to the G protein-coupled receptor family [24][25][26][27] and generates intracellular second messengers. 28 When TRH receptors are ectopically expressed, they have been shown to cross-couple with cAMP and regulate GH secretion by GH-secreting adenomas.…”

Section: Discussionmentioning

confidence: 99%

Gsp mutation in acromegaly and its influence on TRH‐induced paradoxical GH response

Goto

Kinoshita

Oshino

et al. 2013

Clinical Endocrinology

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Thyrotropin-releasing hormone stimulates GTP hydrolysis by membranes from GH4C1 rat pituitary tumor cells.

Abstract: Thyrotropin-releasing hormone (TRH) stimulates prolactin production by GH4C, rat pituitary tumor cells, which possess high-affinity membrane receptors for the peptide. TRH caused up to a 50% increase in the activity of a low-Km GTPase in membranes from GH4Cj cells.

Cited by 61 publications

References 35 publications

Desensitization, Trafficking, and Resensitization of the Pituitary Thyrotropin-Releasing Hormone Receptor

Desensitization, Trafficking, and Resensitization of the Pituitary Thyrotropin-Releasing Hormone Receptor

Mechanism of Thyrotropin Releasing Hormone Stimulation of Pituitary Hormone Secretion

Gsp mutation in acromegaly and its influence on TRH‐induced paradoxical GH response

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