GPR101 drives growth hormone hypersecretion and gigantism in mice via constitutive activation of Gs and Gq/11

Abboud, Dayana; Daly, Adrian; Dupuis, Nadine; Bahri, Mohamed Ali; Inoue, Asuka; Chevigné, Andy; Ectors, Fabien; Plenevaux, Alain; Pirotte, Bernard; Beckers, Albert; Hanson, Julien

doi:10.1038/s41467-020-18500-x

Cited by 34 publications

(17 citation statements)

References 64 publications

(81 reference statements)

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“…1). A recent study in transgenic mice has demonstrated that GPR101 constitutively activates not only G s , but also G q/11 and G 12/13 , leading to GH secretion but not cell proliferation [35]. The pathogenetic mechanism may also involve the ability of GPR101 to increase GHRH secretion by the hypothalamus, accordingly to the elevated circulating GHRH levels described in some X-LAG patients [30, 36, 37].…”

Section: Pathogenesis Of Pitnets: Germline and Somatic Mutationsmentioning

confidence: 99%

Pituitary Tumors: Genetic and Molecular Factors Underlying Pathogenesis and Clinical Behavior

Spada¹,

Mantovani²,

Treppiedi³

et al. 2021

Neuroendocrinology

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Pituitary neuroendocrine tumors (PitNETs) are the most common intracranial neoplasms. Although generally benign, they can show a clinically aggressive course, with local invasion, recurrences and resistance to medical treatment. No universally accepted biomarkers of aggressiveness are available yet, and predicting clinical behavior of PitNETs remains a challenge. In rare cases the presence of germline mutations in specific genes predisposes to PitNETs formation, as part of syndromic diseases or familial isolated pituitary adenomas (FIPA), and associates to more aggressive, invasive and drug resistant tumors. The vast majority of cases is represented by sporadic PitNETs. Somatic mutations in the  subunit of stimulatory G protein gene (gsp) and in the ubiquitin-specific protease 8 (USP8) gene have been recognized as pathogenetic factors in sporadic GH- and ACTH-secreting PitNETs, respectively, without an association with a worse clinical phenotype. Other molecular factors have been found to significantly affect PitNETs drug responsiveness and invasive behavior. These molecules are cytoskeleton and/or scaffold proteins whose alterations prevent proper functioning of the somatostatin and dopamine receptors, targets of medical therapy, or promote the ability of tumor cells to invade surrounding tissues. The aim of the present review is to provide an overview of the genetic and molecular alterations that can contribute to determine PitNETs clinical behavior. Understanding subcellular mechanisms underlying pituitary tumorigenesis and PitNETs clinical phenotype will hopefully lead to identification of new potential therapeutic targets and new markers predicting the behavior and the response to therapeutic treatments of PitNETs.

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Section: Pathogenesis Of Pitnets: Germline and Somatic Mutationsmentioning

confidence: 99%

Pituitary Tumors: Genetic and Molecular Factors Underlying Pathogenesis and Clinical Behavior

Spada¹,

Mantovani²,

Treppiedi³

et al. 2021

Neuroendocrinology

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“…Therefore, they further determined that the case was not X-LAG by high-definition molecular cytogenesis because the duplicated region did not contain the GPR101 gene, which proved that GPR101 was the pathogenic gene from the reverse side [33]. The latest research reported by Abboud et al [19] revealed that GPR101 could promote GH secretion without hyperplasia/tumorigenesis in HEK293 cells, GH3 cells, human somatotropinoma, and transgenic mice with elevated somatotrope Gpr101 expression, which were related to protein kinase C activation. This study showed that GPR101 expression at the mRNA level was significantly higher in X-LAG patients than in normal or acromegaly females, which was almost the same result as a previous study by Trivellin et al [14].…”

Section: Discussionmentioning

confidence: 98%

“…Indeed, the duplication of the G-protein coupled receptor 101 (GPR101) gene is certified to be the definite pathogenesis of X-LAG by Trivellin et al [14] for the first time, and X-LAG can also occur due to somatic mosaicism in males [18]. The latest research shows that GPR101 plays an important role in GH and PRL over secretion but not hyperplasia and tumorigenesis [19]. Lacovazzo et al [20] showed that 9 patients had pituitary adenomas while 3 patients had hyperplasia in the X-LAG cohort.…”

Section: Introductionmentioning

confidence: 99%

A Chinese Case of X-Linked Acrogigantism and Systematic Review

Liang¹,

Gong²,

Liu³

et al. 2020

Neuroendocrinology

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Introduction: To describe a Chinese case of X-linked acrogigantism (X-LAG) and summarize the characteristics and treatment of all reported cases. Methods: Clinical materials and biological samples from a 5-year and 2-month-old female due to “growth acceleration for 4 years” were collected. Array comparative genomic hybrid (aCGH) and further verification were performed. All X-LAG cases from the PubMed and Web of Science databases were collected and summarized using available data. Results: The patient presented accelerating growth since 1 year of age, and her height reached 134.6 cm (+5.24 standard deviation score, SDS) when she was 5 years and 2 months old. She also had coarsening facial features, snoring, and acral enlargement. Growth hormone (GH) was not suppressed by the glucose-GH inhibition test, and insulin-like growth factor 1 (IGF-1) and prolactin levels were elevated. Pituitary magnetic resonance imaging (MRI) revealed a pituitary enlargement with a maximum diameter of 22.3 mm. Octreotide imaging indicated the presence of a pituitary adenoma. The tumor shrank slightly after three courses of somatostatin analog but without clinical or biochemical remissions, of which the GH nadir value was 9.4 ng/ml, and IGF-1 was elevated to 749 ng/ml. Therefore, she underwent transsphenoidal surgery. Immunohistochemistry showed GH-positive and PRL-positive cells in the pituitary adenoma. Xq26.3 microduplication of the patient’s germline DNA was identified by aCGH. Of all 35 reported cases, females accounted for 71.43%. There were 93.10% and 53.83% patients with hyperprolactinemia and hyperinsulinemia, respectively. Pathology showed that 75.00% of cases were adenomas. Ninety percent of cases had germline variants. The clinical and biochemical remission rates were 78.26% and 82.61%, respectively. However, the rate of complication occurrence during therapy reached 80%. Conclusion: It is important to recognize the possibility of X-LAG when a child under 2 years old presents overgrowth. Early diagnosis and treatment are of great importance for better treatment efficacy and clinical outcome.

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“…Another GPCR which has also been characterized by its striatal enrichment and its relationship to adrenergic receptors, is GPR101 [ 248 ]. It is a Gα s , Gα q/11 , and Gα 12/13 coupled receptor and is enriched in the matrix compartment of the striatum [ 248 , 249 ]. Mice lacking GPR101 display higher immobility time in the forced swim test [ 248 ].…”

Section: Orphan Gpcrs Localized In Circuitries Involved In Mddmentioning

confidence: 99%

Update on GPCR-based targets for the development of novel antidepressants

Mantas

Saarinen

et al. 2021

Mol Psychiatry

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Traditional antidepressants largely interfere with monoaminergic transport or degradation systems, taking several weeks to have their therapeutic actions. Moreover, a large proportion of depressed patients are resistant to these therapies. Several atypical antidepressants have been developed which interact with G protein coupled receptors (GPCRs) instead, as direct targeting of receptors may achieve more efficacious and faster antidepressant actions. The focus of this review is to provide an update on how distinct GPCRs mediate antidepressant actions and discuss recent insights into how GPCRs regulate the pathophysiology of Major Depressive Disorder (MDD). We also discuss the therapeutic potential of novel GPCR targets, which are appealing due to their ligand selectivity, expression pattern, or pharmacological profiles. Finally, we highlight recent advances in understanding GPCR pharmacology and structure, and how they may provide new avenues for drug development.

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GPR101 drives growth hormone hypersecretion and gigantism in mice via constitutive activation of Gs and Gq/11

Cited by 34 publications

References 64 publications

Pituitary Tumors: Genetic and Molecular Factors Underlying Pathogenesis and Clinical Behavior

Pituitary Tumors: Genetic and Molecular Factors Underlying Pathogenesis and Clinical Behavior

A Chinese Case of X-Linked Acrogigantism and Systematic Review

Update on GPCR-based targets for the development of novel antidepressants

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