-
Tijdschrift Voor Psychiatrie 2021Current antipsychotic treatment is suboptimal. There is an urgent need for new antipsychotics with new mechanisms of action. SEP-363856 is a trace amine-associated... (Review)
Review
BACKGROUND
Current antipsychotic treatment is suboptimal. There is an urgent need for new antipsychotics with new mechanisms of action. SEP-363856 is a trace amine-associated receptor 1 (TAAR1) agonist and a serotonin 5-HT1a agonist with potential antipsychotic properties.
AIM
To describe the rationale for the development of SEP-363856, the pharmacology of TAAR1/5-HT1a agonists, and the clinical efficacy of SEP-363856.
METHOD
A narrative review of the literature using PubMed, Embase and PsychINFO.
RESULTS
Six publications were identified, one of which was a phase 2 clinical trial with SEP-363856. This phase 2 study shows that SEP-363856 is an effective and well-tolerated antipsychotic; positive, but also negative symptoms decreased; motor side effects (akathisia) and prolactin increase did not occur, while metabolic side effects hardly occurred. Reported side-effects were somnolence and nausea. The antipsychotic activity of SEP-363856 appears to be (pre)clinical not based on D2 antagonism, but on TAAR1 and 5-HT1a agonism.
CONCLUSION
TAAR1 and 5-HT1a agonists such as SEP-363856 may be a treatment option for psychosis. Hopefully they can be further developed into an antipsychotic with a favorable effectiveness and tolerability profile.
Topics: Antipsychotic Agents; Humans; Psychotic Disorders; Receptors, Dopamine; Serotonin 5-HT1 Receptor Agonists; Treatment Outcome
PubMed: 34851520
DOI: No ID Found -
ELife May 2023Class 1 cytokine receptors transmit signals through the membrane by a single transmembrane helix to an intrinsically disordered cytoplasmic domain that lacks kinase...
Class 1 cytokine receptors transmit signals through the membrane by a single transmembrane helix to an intrinsically disordered cytoplasmic domain that lacks kinase activity. While specific binding to phosphoinositides has been reported for the prolactin receptor (PRLR), the role of lipids in PRLR signaling is unclear. Using an integrative approach combining nuclear magnetic resonance spectroscopy, cellular signaling experiments, computational modeling, and simulation, we demonstrate co-structure formation of the disordered intracellular domain of the human PRLR, the membrane constituent phosphoinositide-4,5-bisphosphate (PI(4,5)P) and the FERM-SH2 domain of the Janus kinase 2 (JAK2). We find that the complex leads to accumulation of PI(4,5)P at the transmembrane helix interface and that the mutation of residues identified to interact specifically with PI(4,5)P negatively affects PRLR-mediated activation of signal transducer and activator of transcription 5 (STAT5). Facilitated by co-structure formation, the membrane-proximal disordered region arranges into an extended structure. We suggest that the co-structure formed between PRLR, JAK2, and PI(4,5)P locks the juxtamembrane disordered domain of the PRLR in an extended structure, enabling signal relay from the extracellular to the intracellular domain upon ligand binding. We find that the co-structure exists in different states which we speculate could be relevant for turning signaling on and off. Similar co-structures may be relevant for other non-receptor tyrosine kinases and their receptors.
Topics: Humans; Carrier Proteins; Janus Kinase 2; Phosphorylation; Prolactin; Receptors, Prolactin; Signal Transduction; STAT5 Transcription Factor
PubMed: 37232489
DOI: 10.7554/eLife.84645 -
Seminars in Cell & Developmental Biology Jun 2021Prolactin has a rich mechanistic set of actions and signaling in order to elicit developmental effects in mammals. Historically, prolactin has been appreciated as an... (Review)
Review
Prolactin has a rich mechanistic set of actions and signaling in order to elicit developmental effects in mammals. Historically, prolactin has been appreciated as an endocrine peptide hormone that is responsible for final, functional mammary gland development and lactation. Multiple signaling pathways impacted upon by the microenvironment contribute to cell function and differentiation. Endocrine, autocrine and paracrine signaling are now apparent in not only mammary development, but also in cancer, and involve multiple cell types including those of the immune system. Multiple ligands agonists are capable of binding to the prolactin receptor, potentially expanding receptor function. Prolactin has an important role not only in tumorigenesis of the breast, but also in a number of hormonally responsive cancers such as prostate, ovarian and endometrial cancer, as well as pancreatic and lung cancer. Although pituitary and extra-pituitary sources of prolactin such as the epithelium are important, stromal sourced prolactin is now also being recognized as an important factor in tumor progression, all of which potentially signal to multiple cell types in the tumor microenvironment. While prolactin has important roles in milk production including calcium and bone homeostasis, in the disease state it can also affect bone homeostasis. Prolactin also impacts metastatic cancer of the breast to modulate the bone microenvironment and promote bone damage. Prolactin has a fascinating contribution in both physiologic and pathologic settings of mammals.
Topics: Animals; Disease Models, Animal; Female; Humans; Mammary Glands, Animal; Mammary Glands, Human; Mice; Neoplasm Metastasis; Neoplasms; Prolactin
PubMed: 33109441
DOI: 10.1016/j.semcdb.2020.10.005 -
Frontiers in Endocrinology 2021Prolactin (PRL) is a hormone produced by the pituitary gland and multiple non-pituitary sites, vital in several physiological processes such as lactation, pregnancy,... (Review)
Review
Prolactin (PRL) is a hormone produced by the pituitary gland and multiple non-pituitary sites, vital in several physiological processes such as lactation, pregnancy, cell growth, and differentiation. However, PRL is nowadays known to have a strong implication in oncogenic processes, making it essential to delve into the mechanisms governing these actions. PRL and its receptor (PRLR) activate a series of effects such as survival, cellular proliferation, migration, invasion, metastasis, and resistance to treatment, being highly relevant in developing certain types of cancer. Because women produce high levels of PRL, its influence in gynecological cancers is herein reviewed. It is interesting that, other than the 23 kDa PRL, whose mechanism of action is endocrine, other variants of PRL have been observed to be produced by tumoral tissue, acting in a paracrine/autocrine manner. Because many components, including PRL, surround the microenvironment, it is interesting to understand the hormone's modulation in cancer cells. This work aims to review the most important findings regarding the PRL/PRLR axis in cervical, ovarian, and endometrial cancers and its molecular mechanisms to support carcinogenesis.
Topics: Cell Transformation, Neoplastic; Female; Genital Neoplasms, Female; Humans; Prolactin; Receptors, Prolactin; Signal Transduction; Tumor Microenvironment
PubMed: 34745013
DOI: 10.3389/fendo.2021.747810 -
Expert Opinion on Therapeutic Targets Nov 2020: Prolactin (PRL) and its receptor (PRLR) have been associated with the development of hormone-dependent tumors and have been detected in glioblastoma (GBM) biopsies.... (Review)
Review
: Prolactin (PRL) and its receptor (PRLR) have been associated with the development of hormone-dependent tumors and have been detected in glioblastoma (GBM) biopsies. GBM is the most common and aggressive primary brain tumor in adults and the prognosis for patients is dismal; hence researchers are exploring the PRLR pathway as a therapeutic target in this disease. : This paper explores the effects of PRLR activation on the biology of GBM, the correlation between PRL and PRLR expression and GBM progression and survival in male and female patients. Finally, we discuss how a better understanding of the PRLR pathway may allow the development of novel treatments for GBM. : We propose PRL and PRLR as potential prognosis biomarkers and therapeutic targets in GBM. Local administration of PRLR inhibitors using gene therapy may offer a beneficial strategy for targeting GBM cells disseminated in the non-neoplastic brain; however, efficacy and safety require careful and extensive evaluation. The data depicted herein underline the need to (i) improve our understanding of sexual dimorphism in GBM, and (ii) develop accurate preclinical models that take into consideration different hormonal contexts, specific genetic alterations, and tumor grades.
Topics: Adult; Animals; Biomarkers, Tumor; Brain Neoplasms; Female; Genetic Therapy; Glioblastoma; Humans; Male; Molecular Targeted Therapy; Prognosis; Prolactin; Receptors, Prolactin
PubMed: 32896197
DOI: 10.1080/14728222.2020.1821187 -
Animal Biotechnology Dec 2023The objectives of the current study were to identify polymorphism in the prolactin receptor (PRLR) gene among three Egyptian goat breeds (Zaraibi, Damascus, and Barki)...
The objectives of the current study were to identify polymorphism in the prolactin receptor (PRLR) gene among three Egyptian goat breeds (Zaraibi, Damascus, and Barki) and to investigate the association between PRLR genotype, parity, season of kidding, and litter size factors with milk yield and reproductive traits of Zaraibi goats. One hundred and ninety blood samples were collected for DNA extraction, with 110 from Zaraibi, 40 from Barki, and 40 from Damascus breeds. Three genotypes, CC, CT and TT, for the prolactin receptor gene were identified in the 190 DNA samples using restriction fragment length polymorphism and were confirmed by direct sequencing technique. Milk yield during suckling and lactation periods in addition to age at first conception, gestation length, and litter size were determined in 110 Zaraibi goats. The Zaraibi goats recorded the highest heterozygosity (0.495) and the effective number of alleles (1.972). The g.62130C > T SNP showed a significant association ( < 0.01) with suckling, lactation, and total milk yield of Zaraibi goats with the highest values recorded at the third parity. Age at the first conception and gestation length traits were significantly influenced by the kidding season ( < 0.05) with younger age in autumn and shorter length in spring seasons. Milk yield during the suckling period was significantly ( < 0.01) higher in the case of triplets' litter size. The current study showed that litter size and parity played an important role in the amount of Zaraibi goats' milk yield. The g.62130C > T SNP of the PRLR gene may be a useful marker for assisted selection programs to improve goat milk yield during suckling and lactation periods with the heterozygous genotype CT recording the highest values.
Topics: Pregnancy; Female; Animals; Receptors, Prolactin; Alleles; Prolactin; Goats; Egypt; Milk; DNA
PubMed: 37409468
DOI: 10.1080/10495398.2023.2223237 -
Biologie Aujourd'hui 2022Prolactin (PRL) is a polypeptide hormone that is mainly synthesized and secreted by lactotroph cells of the anterior pituitary gland. The actions of prolactin are...
Prolactin (PRL) is a polypeptide hormone that is mainly synthesized and secreted by lactotroph cells of the anterior pituitary gland. The actions of prolactin are mediated by its transmembrane receptor, PRLR. The principal role attributed to PRL is to stimulate the proliferation and differentiation of the mammary cells required for lactation, but studies of animal models have assigned more than 300 separate actions to this hormone in various species. Hyperprolactinaemia is the prototypical pathological state associated with this hormone. Indeed, hyperprolactinaemia is the most common cause of amenorrhoea due to hypogonadotropic anovulation and is one of the most prevalent endocrine causes of infertility in women. In recent years, the study of conditional or complete Prlr mouse models had improved the understanding concerning the regulation of gonadotroph and lactotroph axes. It is now demonstrated that prolactin exerts autocrine or paracrine actions on lactotroph cells in vivo. One of the major advances was to better understand, using mouse models, the impact of hyperprolactinemia on gonadotroph axis. It is now accepted that hypogonadotropic hypogonadism in patients with hyperprolactinemia is mediated by a decrease of hypothalamic kisspeptin secretion. Gonadotroph axis can be restored by intravenous administration of kisspeptin. However, the mechanisms of lactotroph tumorigenesis in Prlr animals remain incompletely understood and transposable to the human species, since the only patient with biallelic PRLR loss-of-function mutation leading to complete prolactin resistance that has been described so far did not have pituitary adenoma visible on MRI.
Topics: Animals; Female; Humans; Mice; Hyperprolactinemia; Kisspeptins; Models, Animal; Prolactin; Receptors, Prolactin
PubMed: 36744975
DOI: 10.1051/jbio/2022019 -
International Journal of Medical... 2020Prolactinomas are the most common type of functional pituitary adenoma. Although bromocriptine is the preferred first line treatment for prolactinoma, resistance... (Observational Study)
Observational Study
Prolactinomas are the most common type of functional pituitary adenoma. Although bromocriptine is the preferred first line treatment for prolactinoma, resistance frequently occurs, posing a prominent clinical challenge. Both the prolactin receptor (PRLR) and estrogen receptor α (ERα) serve critical roles in the development and progression of prolactinomas, and whether this interaction between PRLR and ERα contributes to bromocriptine resistance remains to be clarified. In the present study, increased levels of ERα and PRLR protein expression were detected in bromocriptine-resistant prolactinomas and MMQ cells. Prolactin (PRL) and estradiol (E2) were found to exert synergistic effects on prolactinoma cell proliferation. Furthermore, PRL induced the phosphorylation of ERα via the JAK2-PI3K/Akt-MEK/ERK pathway, while estrogen promoted PRLR upregulation via pERα. ERα inhibition abolished E2-induced PRLR upregulation and PRL-induced ERα phosphorylation, and fulvestrant, an ERα inhibitor, restored pituitary adenoma cell sensitivity to bromocriptine by activating JNK-MEK/ERK-p38 MAPK signaling and cyclin D1 downregulation. Collectively, these data suggest that the interaction between the estrogen/ERα and PRL/PRLR pathways may contribute to bromocriptine resistance, and therefore, that combination treatment with fulvestrant and bromocriptine (as opposed to either drug alone) may exert potent antitumor effects on bromocriptine-resistant prolactinomas.
Topics: Adolescent; Adult; Animals; Antineoplastic Combined Chemotherapy Protocols; Bromocriptine; Cell Line, Tumor; Cyclin D1; Drug Resistance, Neoplasm; Estradiol; Estrogen Receptor alpha; Female; Fulvestrant; Humans; Hypophysectomy; MAP Kinase Signaling System; Male; Middle Aged; Neoplasm Recurrence, Local; Pituitary Gland; Pituitary Neoplasms; Prolactin; Prolactinoma; Rats; Receptors, Prolactin; Young Adult
PubMed: 33173437
DOI: 10.7150/ijms.51176 -
Frontiers in Cell and Developmental... 2023Decidualization is considered a distinctive feature of eutherian pregnancy, and has appeared during evolution along with the development of invasive forms of... (Review)
Review
Decidualization is considered a distinctive feature of eutherian pregnancy, and has appeared during evolution along with the development of invasive forms of placentation, as the endotheliochorial placenta. Although decidualization is not massive in carnivores, as it is in most species developing hemochorial placentas, isolated or grouped cells regarded as decidual have been documented and characterized, mainly in bitches and queens. For the majority of the remaining species of the order, data in the bibliography are fragmentary. In this article, general morphological aspects of decidual stromal cells (DSCs), their time of appearance and lasting, data about the expression of cytoskeletal proteins and molecules considered as markers of decidualization were reviewed. From the data reviewed, it follows that carnivoran DSCs take part either in the secretion of progesterone, prostaglandins, relaxin, among other substances, or at least in the signaling pathways triggered by them. Beyond their physiological roles, some of those molecules are already being used, or are yet under study, for the non-invasive endocrine monitoring and reproductive control of domestic and wild carnivores. Only insulin-like growth factor binding protein 1, among the main decidual markers, has been undoubtedly demonstrated in both species. Laminin, on the contrary, was found only in feline DSCs, and prolactin was preliminary reported in dogs and cats. Prolactin receptor, on the other hand, was found in both species. While canine DSCs are the only placental cell type expressing the nuclear progesterone receptor (PGR), that receptor has not been demonstrated neither in feline DSCs, nor in any other cell in the queen placenta, although the use of PGR blockers leads to abortion. Against this background, and from the data gathered so far, it is unquestionable that DSCs in carnivorans do play a pivotal role in placental development and health. The knowledge about placental physiology is critical for medical care and breeding management, primarily in domestic carnivores; it is also absolutely crucial for a conservation approach in the management of endangered carnivore species.
PubMed: 37009475
DOI: 10.3389/fcell.2023.1134874 -
Scientific Reports Dec 2019Although prolactin (PRL) and its receptor (PRLR) have been detected in glioblastoma multiforme (GBM), their role in its pathogenesis remains unclear. Our aim was to...
Although prolactin (PRL) and its receptor (PRLR) have been detected in glioblastoma multiforme (GBM), their role in its pathogenesis remains unclear. Our aim was to explore their contribution in GBM pathogenesis. We detected PRL and PRLR in all GBM cell lines tested. PRLR activation or overexpression using plasmid transfection increased proliferation, viability, clonogenicity, chemoresistance and matrix metalloproteinase activity in GBM cells, while PRLR antagonist ∆1-9-G129R-hPRL reduced their proliferation, viability, chemoresistance and migration. Meta-analysis of transcriptomic data indicated that PRLR was expressed in all grade II-III glioma (GII-III) and GBM samples. PRL was upregulated in GBM biopsies when compared to GII-III. While in the general population tumour PRL/PRLR expression did not correlate with patient survival, biological sex-stratified analyses revealed that male patients with PRL/PRLR GBM performed worse than PRL/PRLR GBM. In contrast, all male PRL/PRLR GII-III patients were alive whereas only 30% of PRL/PRLR GII-III patients survived after 100 months. Our study suggests that PRLR may be involved in GBM pathogenesis and could constitute a therapeutic target for its treatment. Our findings also support the notion that sexual dimorphism should be taken into account to improve the care of GBM patients.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Cell Proliferation; Female; Glioblastoma; Glioma; Humans; Male; Plasmids; Prolactin; Protein Binding; Rats; Receptors, Prolactin; Signal Transduction; Treatment Outcome
PubMed: 31862900
DOI: 10.1038/s41598-019-55860-x