Many or too many progesterone membrane receptors? Clinical implications

Wendler, Alexandra; Wehling, Martin

doi:10.1016/j.tem.2022.10.001

Cited by 15 publications

(12 citation statements)

References 172 publications

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“…mPR-dependent nongenomic is an important regulator of many physiological processes in female and male reproduction, cardiovascular, neuroendocrine, neurological and immune function (3, 6, 9, 12). This raises interest in mPRs as potential therapeutic targets for hypertension and other cardiovascular diseases, reproductive disorders, neurological diseases, and cancer (12). Therefore, understanding mPR signaling is important to assess their physiological and pathological contributions.…”

Section: Discussionmentioning

confidence: 99%

“…The lipase α/β hydrolase domain-containing protein 2 (ABHD2), an integral plasma membrane protein belonging to the ABHD family, was identified as a membrane progesterone receptor in human sperm (12, 26) ABHD2 acts a monoacyl glycerol lipase (MAGL) that hydrolyses 2-arachidonoylglycerol (2-AG) forming arachidonic acid (AA) and glycerol and leads to sperm activation (26). ABHD2 has also been implicated in follicular maturation in mammals (27), vascular smooth muscle migration, and in pulmonary emphysema (28, 29).…”

Section: Introductionmentioning

confidence: 99%

“…Currently, mPRs mediated signaling is recognized as an important regulator of many biological functions in the nervous and cardiovascular systems, female and male reproductive tissues, intestine, immune and cancer cells, and glucose homeostasis (3,6,(9)(10)(11). Thus, mPRs are emerging as potential clinical targets for hypertension, reproductive disorders, and neurological diseases (12). However, their downstream signaling events are not well defined.…”

Section: Introductionmentioning

confidence: 99%

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Progesterone induces meiosis through two obligate co-receptors with PLA2 activity

Nader,

Assaf,

Zarif

et al. 2023

Preprint

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The steroid hormone progesterone (P4) regulates multiple aspects of reproductive and metabolic physiology. Classical P4 signaling operates through nuclear receptors that regulate transcription of target genes. In addition, P4 signals through membrane P4 receptors (mPRs) in a rapid nongenomic modality. Despite the established physiological importance of P4 nongenomic signaling, its detailed signal transduction remains elusive. Here, usingXenopusoocyte maturation as a well-established physiological readout of nongenomic P4 signaling, we identify the lipid hydrolase ABHD2 (α/β hydrolase domain-containing protein 2) as an essential mPRβ co-receptor to trigger meiosis. We show using functional assays coupled to unbiased and targeted cell-based lipidomics that ABHD2 possesses a phospholipase A2 (PLA2) activity that requires both P4 and mPRβ. This PLA2 activity bifurcates P4 signaling by inducing mPRβ clathrin-dependent endocytosis and producing lipid messengers that are G-protein coupled receptors agonists. Therefore, P4 drives meiosis by inducing the ABHD2 PLA2 activity that requires both mPRβ and ABHD2 as obligate co-receptors.Significance StatementNongenomic progesterone signaling is important for many physiological functions yet its detailed early signaling steps remain elusive. Here we show that progesterone induces rapid signaling to driveXenopusoocyte meiosis. Progesterone requires two cell membrane receptor to work in unison to signal. The co-receptor complex possesses lipase activity that produces lipid messenger and changes cell membrane structure. This leads to receptor endocytosis and activation of additional pathway to trigger meiosis. Nongenomic progesterone signaling operates in every tissue and regulates reproductive and metabolic physiology. Therefore, our findings have broad implications on our understanding of nongenomic progesterone signaling.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Progesterone induces meiosis through two obligate co-receptors with PLA2 activity

Nader,

Assaf,

Zarif

et al. 2023

Preprint

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“…Non-classical progesterone actions are mediated by non-nuclear PR, which belongs to the membrane-associated progesterone receptor (MAPR) family. This includes progesterone receptor membrane component 1 (PGRMC1) and PGRMC2, which are expressed in several reproductive organs including the placenta and ovary [ 36 ]. So far, progesterone binding has only been tested for PGRMC1, although the specific binding sites have not yet been identified.…”

Section: Progesterone Signaling In Uterine Fibroid Pathogenesismentioning

confidence: 99%

Progesterone Signaling and Uterine Fibroid Pathogenesis; Molecular Mechanisms and Potential Therapeutics

Ali

Ciebiera

Vafaei

et al. 2023

Cells

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Uterine fibroids (UFs) are the most important benign neoplastic threat to women’s health worldwide, with a prevalence of up to 80% in premenopausal women, and can cause heavy menstrual bleeding, pain, and infertility. Progesterone signaling plays a crucial role in the development and growth of UFs. Progesterone promotes the proliferation of UF cells by activating several signaling pathways genetically and epigenetically. In this review article, we reviewed the literature covering progesterone signaling in UF pathogenesis and further discussed the therapeutic potential of compounds that modulate progesterone signaling against UFs, including selective progesterone receptor modulator (SPRM) drugs and natural compounds. Further studies are needed to confirm the safety of SPRMs as well as their exact molecular mechanisms. The consumption of natural compounds as a potential anti-UFs treatment seems promising, since these compounds can be used on a long-term basis—especially for women pursuing concurrent pregnancy, unlike SPRMs. However, further clinical trials are needed to confirm their effectiveness.

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“…Specifically, the activation of S2R/TMEM97 promotes cancer cell apoptosis resulting in anticancer activity, while the inhibition or antagonism of the S2R/TMEM97 has a role in neuroprotection, neurodegeneration, improved cognition, and anti-dementia. Elayta (CT1812), a small-molecule S2R antagonist which binds to the receptors at the progesterone receptor membrane component 1 subunit, is currently under phase II clinical trial in patients with mild to moderate Alzheimer’s disease. , Ligands for the S2R/PGRMC1 receptor are reported to be negative allosteric regulators that reduce the affinity of oligomeric Aβ for its receptor, and thus interfere with Aβ-induced synaptic toxicity . Also, roluperidone (MIN-101) is a compound with S2R, 5-HT 2A and α 1A -adrenergic receptor antagonist profile in phase III clinical trials for the treatment of negative symptoms of schizophrenia. , …”

Section: Introductionmentioning

confidence: 99%

Synthesis, Computational Insights, and Evaluation of Novel Sigma Receptors Ligands

Dichiara

Ambrosio

Barbaraci

et al. 2023

ACS Chem. Neurosci.

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The development of diazabicyclo[4.3.0]nonane and 2,7-diazaspiro[3.5]nonane derivatives as sigma receptors (SRs) ligands is reported. The compounds were evaluated in S1R and S2R binding assays, and modeling studies were carried out to analyze the binding mode. The most notable compounds, 4b (AD186, K iS1R = 2.7 nM, K iS2R = 27 nM), 5b (AB21, K iS1R = 13 nM, K iS2R = 102 nM), and 8f (AB10, K iS1R = 10 nM, K iS2R = 165 nM), have been screened for analgesic effects in vivo, and their functional profile was determined through in vivo and in vitro models. Compounds 5b and 8f reached the maximum antiallodynic effect at 20 mg/kg. The selective S1R agonist PRE-084 completely reversed their action, indicating that the effects are entirely dependent on the S1R antagonism. Conversely, compound 4b sharing the 2,7-diazaspiro[3.5]nonane core as 5b was completely devoid of antiallodynic effect. Interestingly, compound 4b fully reversed the antiallodynic effect of BD-1063, indicating that 4b induces an S1R agonistic in vivo effect. The functional profiles were confirmed by the phenytoin assay. Our study might establish the importance of 2,7-diazaspiro[3.5]nonane core for the development of S1R compounds with specific agonist or antagonist profile and the role of the diazabicyclo[4.3.0]nonane in the development of novel SR ligands.

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Many or too many progesterone membrane receptors? Clinical implications

Cited by 15 publications

References 172 publications

Progesterone induces meiosis through two obligate co-receptors with PLA2 activity

Progesterone induces meiosis through two obligate co-receptors with PLA2 activity

Progesterone Signaling and Uterine Fibroid Pathogenesis; Molecular Mechanisms and Potential Therapeutics

Synthesis, Computational Insights, and Evaluation of Novel Sigma Receptors Ligands

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