Involvement of G Protein-coupled Receptor Kinase 5 in Homologous Desensitization of the Thyrotropin Receptor

Nagayama, Yuji; Tanaka, Kunihiko; Hara, Takeshi; Namba, Hiroyuki; Yamashita, Shunichi; Taniyama, Kohtaro; Níwa, Masami

doi:10.1074/jbc.271.17.10143

Cited by 64 publications

(38 citation statements)

References 40 publications

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“…Expression of GRKs 2, 5 and 6 has previously been demonstrated in rat and human thyroid tissue and in FRTL 5 cells (Iacovelli et al 1996, Nagayama et al 1996a,b, Metaye et al 2002. In addition to GRKs 2, 5 and 6, we identified GRKs 3 and 4 in the human thyroid using RT-PCR and Western blot (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Although several authors have recently demonstrated an influence of GRK 2, GRK 5, GRK 6 and -arrestin 1 on the desensitization of the rat TSHR in vitro (Iacovelli et al 1996, Nagayama et al 1996a, the distinct molecular mechanism of TSHR desensitization remains unclear. However, an involvement at different steps of the desensitization machinery of the TSHR has been suspected in thyroid pathologies (Kopp 1997) including differentiated thyroid carcinoma cells (Metaye et al 2002).…”

Section: Introductionmentioning

confidence: 99%

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Increased expression of G-protein-coupled receptor kinases 3 and 4 in hyperfunctioning thyroid nodules

Voigt

Holzapfel²,

Meyer³

et al. 2004

Journal of Endocrinology

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G-protein-coupled receptor kinases (GRKs) are implicated in the pathophysiology of human diseases such as arterial hypertension, heart failure and rheumatoid arthritis. While G-protein-coupled receptor kinases 2 and 5 have been shown to be involved in the desensitization of the rat thyrotropin receptor (TSHR), their role in the pathophysiology of hyperfunctioning thyroid nodules (HTNs) is unknown. Therefore, we analyzed the expression pattern of the known GRKs in human thyroid tissue and investigated their function in the pathology of HTNs. The expression of different GRKs in human thyroid and HTNs was measured by Western blotting. The influence of GRK expression on TSHR function was analyzed by coexpression experiments in HEK 293 cells. We demonstrate that in addition to GRKs 2, 5 and 6, GRKs 3 and 4 are also expressed in the human thyroid. GRKs 2, 3, 5 and 6 are able to desensitize the TSHR in vitro. This GRKinduced desensitization is amplified by the additional over-expression of -arrestin 1 or 2. We did not find any mutations in the GRKs 2, 3 and 5 from 14 HTNs without TSHR mutations and G s mutations. The expression of GRKs 3 and 4 was increased in HTNs independently from the existence of TSHR mutations or G s mutations.In conclusion, the increased expression of GRK 3 in HTNs and the ability of GRK 3 to desensitize the TSHR in vitro, suggest a potential role for GRK 3 as a negative feedback regulator for the constitutively activated cAMP pathway in HTNs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Increased expression of G-protein-coupled receptor kinases 3 and 4 in hyperfunctioning thyroid nodules

Voigt

Holzapfel²,

Meyer³

et al. 2004

Journal of Endocrinology

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“…GRK2, GRK6 and dominant-negative GRK2 were ineffective. Using full-length antisense constructs for GRK5 and GRK6 stably expressed in FRTL5 rat thyroid cells, Nagayama et al [34] showed a selective inhibition of thyrotropin receptor desensitization in GRK5-deficient, but not GRK6-deficient, cells. Initial studies from GRK5 2/2 knockout mice showed an enhanced sensitivity to the central administration of the muscarinic receptor agonist oxotremorine [35].…”

Section: Grk5mentioning

confidence: 99%

Non-visual GRKs: are we seeing the whole picture?

Willets

Challiss

Nahorski

2003

Trends in Pharmacological Sciences

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G-protein-coupled receptor kinases (GRKs) comprise a family of seven mammalian serine/threonine protein kinases that phosphorylate and regulate agonist-occupied or constitutively active G-protein-coupled receptors (GPCRs). Studies of the details and consequences of these mechanisms have focused heavily on the original b-adrenoceptor kinase (b-ARK) family (GRK2 and GRK3) and, in particular, on phosphorylation-dependent recruitment of adaptor proteins such as the b-arrestins. However, recent work has indicated roles for the other, non-visual GRKs (GRK4, GRK5 and GRK6) and has revealed potential phosphorylation-independent regulation of GPCRs by GRK2 and GRK3. In this article, we review this newer information and attempt to put it into context with GRKs as physiological regulators that could be appropriate targets for future pharmacological intervention.G-protein-coupled receptors (GPCRs) constitute a very large family of heptahelical, integral membrane proteins that mediate a wide variety of physiological processes ranging from the transmission of light and odorant signals to the mediation of neurotransmission and hormonal actions [1,2]. GPCRs represent a major target for therapeutic agents, and the continuing identification of orphan GPCRs offers opportunity for future pharmacological and therapeutic development [3].Most GPCRs display a rapid loss of responsiveness in the continuing (or recurring) presence of an agonist or stimulus, and there is now substantial evidence that this process of desensitization, at least in part, is a consequence of ligand-induced phosphorylation of serine and threonine residues located within the C-terminal domain and/or the third intracellular loop of GPCRs. Two families of protein kinases appear to be predominantly involved: the G-protein-coupled receptor kinases (GRKs), which phosphorylate agonist-occupied GPCRs to mediate homologous receptor phosphorylation, and the second messengeractivated kinases, such as cAMP-dependent kinase (PKA) and protein kinase C (PKC), which can phosphorylate both ligand-bound and other inactive GPCRs in a heterologous manner [4,5]. Phosphorylation by GRKs enhances receptor affinity for non-visual b-arrestins 1 and 2 (arrestin2 and arrestin3), which not only sterically suppresses further interaction between the receptor and G proteins, but also initiates clathrin-mediated endocytosis of phosphorylated receptors and can promote the activation of additional signalling pathways by acting as agonist-regulated adaptor scaffolds [6].Other protein kinases have also been implicated in GPCR regulation. For example, evidence has accumulated that casein kinase 1a might bring about agonistmediated phosphorylation of acetylcholine muscarinic M 3 receptors and light-activated rhodopsin [7]. Casein kinase 1a-mediated phosphorylation does not appear to be associated with reduced responsiveness of the M 3 receptor but probably contributes to the activation of extracellular signal-regulated kinases 1 and 2 (ERK1,2) by this receptor [8,9].Although research in this area h...

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“…For example, both GRK2 and GRK5 are expressed in heart, and both GRKs can target the ␤-adrenergic receptor (5). The relative importance of each GRK expressed in the same tissue may be tested by antisense transfection (6,7), treatment with monoclonal antibodies (4), or a transgene technique (8,9).…”

mentioning

confidence: 99%

G Protein-coupled Receptor Kinase 5 in Cultured Vascular Smooth Muscle Cells and Rat Aorta

Ishizaka

Alexander

Laursen

et al. 1997

Journal of Biological Chemistry

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GRK5, a recently cloned member of the G proteincoupled receptor kinase family, has been shown to phosphorylate and participate in the desensitization of angiotensin II (Ang II) type 1A (AT 1A ) receptors. In this study, the effect of angiotensin II on GRK5 expression was examined in cultured vascular smooth muscle cells and aortas of Ang II-infused hypertensive rats. In vascular smooth muscle cells, Ang II (100 nM) up-regulated GRK5 mRNA as early as 1 h, with a peak at 16 h. This up-regulation was dose-and calcium-dependent. The increase in GRK5 mRNA was reflected in a smaller increase in protein expression, which nonetheless had functional significance since AT 1 receptor phosphorylation was increased and phospholipase C activation was decreased following prolonged incubation with Ang II. In aortas of Ang II-infused hypertensive rats, both GRK5 mRNA and protein levels increased ϳ3-fold compared with sham-operated rats at 5 and 7 days, respectively. This up-regulation was blocked either by losartan or by the nonspecific vasodilator hydralazine. Since a subpressor dose of Ang II did not increase GRK5 mRNA levels and norepinephrine infusion also increased GRK5 mRNA expression, we conclude that Ang II-induced GRK5 up-regulation in rat aortas may be due to hypertension per se. Hormone-and hemodynamic stress-induced GRK5 regulation may provide a novel molecular basis for long-term regulation of agonist sensitivity of vascular cells. G protein-coupled receptor kinases (GRKs)1 are a recently identified family of enzymes that phosphorylate seven-transmembrane receptors. Receptor phosphorylation by GRKs subsequently promotes the binding of the regulatory arrestin protein, which results in uncoupling of the receptor and G protein (1). Six different mammalian GRKs have so far been cloned and characterized. Although GRK1 (rhodopsin kinase) and GRK4 are expressed exclusively in retinal photoreceptor cells and testis, respectively, ␤-adrenergic receptor kinase 1 (GRK2) and ␤-adrenergic receptor kinase 2 (GRK3), as well as GRK5 and GRK6, are widely distributed throughout the body. The range of substrates on which they may act and the mechanisms that regulate their expression are largely unknown.GRK5 is expressed in heart, placenta, lung, and skeletal muscle. GRK5 phosphorylates ␤ 1 -adrenergic, muscarinic, ␦-opioid, and angiotensin II (Ang II) type 1A (AT 1A ) receptors (1-4). In the same tissue or cell, two or more GRKs may be present and may target the same G protein-coupled receptors. For example, both GRK2 and GRK5 are expressed in heart, and both GRKs can target the ␤-adrenergic receptor (5). The relative importance of each GRK expressed in the same tissue may be tested by antisense transfection (6, 7), treatment with monoclonal antibodies (4), or a transgene technique (8, 9).Vascular smooth muscle cells (VSMC) express high levels of AT 1A receptors that rapidly desensitize coupling to phospholipase C upon agonist stimulation (10). These receptors also couple to phospholipase D, a response that continues for as long as th...

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Involvement of G Protein-coupled Receptor Kinase 5 in Homologous Desensitization of the Thyrotropin Receptor

Cited by 64 publications

References 40 publications

Increased expression of G-protein-coupled receptor kinases 3 and 4 in hyperfunctioning thyroid nodules

Increased expression of G-protein-coupled receptor kinases 3 and 4 in hyperfunctioning thyroid nodules

Non-visual GRKs: are we seeing the whole picture?

G Protein-coupled Receptor Kinase 5 in Cultured Vascular Smooth Muscle Cells and Rat Aorta

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