Estrogen receptors (ERs) and their ligands play a crucial role in physiological and pathophysiological processes, particularly in the central nervous and cardiovascular systems. There is increasing evidence that besides the two cytosolic and nuclear ERs, namely, ERα and ERβ, the seven-transmembrane G protein-coupled ER 1 (GPER1) is of great importance in the molecular mechanisms underlying various neurological and cardiovascular diseases and is probably responsible for sex-specific differences. In contrast to ERα and ERβ, GPER1 mediates its effects through not only transcriptional regulation but also rapid nongenomic signaling. This emphasizes the role of GPER1 in the modulation of acute pathophysiological mechanisms involving changes in diverse signaling pathways related to neurological and cardiological aspects. In this review, we have summarized the role of GPER1 in disorders of excitable tissues, including neuroinflammation, learning and memory, Alzheimer’s disease, Parkinson’s disease, depression and mood disorders, schizophrenia, epilepsy, autism spectrum disorders and attention-deficit/hyperactivity disorder, migraine and pain, cardiovascular hypertension, cardiovascular function and fibrosis, hypertrophy, and atrial fibrillation, with a special focus on its involvement in sex-specific differences. We have assessed reports investigating the role of GPER1 in rodents and humans using in vivo and in vitro data. We have also reviewed the role of nutraceuticals, especially phytoestrogens, in this context. Furthermore, we have discussed the potential of GPER1 as a target for novel therapeutic interventions and prognostic indicator of neurological and cardiovascular diseases with a focus on sex-specific differences.

A disintegrin and metalloproteinase (ADAM) family proteins, acting as sheddases, are important factors in a number of pathologies, including cancer, and have been suggested as promising therapeutic targets. The study presented focuses on the involvement of ADAM10 and ADAM17 in retinoblastoma (RB), the most common malignant intraocular childhood tumor. A significant correlation between ADAM17 expression levels and RB laterality and RB staging was observed. Levels of ADAM10 or ADAM17 regulating miRNAs miR-145, -152, and -365 were significantly downregulated in RB cell lines, and reduced miR levels with simultaneously upregulated ADAM10 and ADAM17 expression were found in RB patients. The involvement of both ADAMs analyzed in ectodomain shedding of the neuronal cell adhesion molecule L1 (L1CAM), shown to induce pro-tumorigenic effects in RB, was confirmed. Lentiviral ADAM10 and ADAM17 single or ADAM10/17 double knockdown (KD) induced caspase-dependent apoptosis and reduced cell viability, proliferation, growth, and colony formation capacity of RB cells. Moreover, differential phosphorylation of the serine/threonine kinase AKT was observed following ADAM17 KD in RB cells. Chicken chorioallantoic membrane (CAM) assays revealed that ADAM17 and ADAM10/17 depletion decreases the tumorigenic and migration potential of RB cells in vivo. Thus, ADAMs are potential novel targets for future therapeutic RB approaches.

Protein tyrosine phosphatase receptor type E (PTPRE) is a member of the “classical” protein tyrosine phosphatase subfamily and regulates a variety of cellular processes in a tissue-specific manner by antagonizing the function of protein tyrosine kinases. PTPRE plays a tumorigenic role in different human cancer cells, but its role in retinoblastoma (RB), the most common malignant eye cancer in children, remains to be elucidated. Etoposide-resistant RB cell lines and RB patients display significant higher PTPRE expression levels compared to chemosensitive counterparts and the healthy human retina, respectively. PTPRE promotor methylation analyses revealed that PTPRE expression in RB is not regulated via this mechanism. Lentiviral PTPRE knockdown (KD) induced a significant decrease in growth kinetics, cell viability, and anchorage-independent growth of etoposide-resistant Y79 and WERI RB cells. Caspase-dependent apoptosis rates were significantly increased and a re-sensitization for etoposide could be observed after PTPRE depletion. In vivo chicken chorioallantoic membrane (CAM) assays revealed decreased tumor formation capacity as well as reduced tumor size and weight following PTPRE KD. Expression levels of miR631 were significantly downregulated in etoposide-resistant RB cells and patients. Transient miR631 overexpression resulted in significantly decreased PTPRE levels and concomitantly decreased proliferation and increased apoptosis levels in etoposide-resistant RB cells. These impacts mirror PTPRE KD effects, indicating a regulation of PTPRE via this miR. Additionally, PTPRE KD led to altered phosphorylation of protein kinase SGK3 and—dependent on the cell line—AKT and ERK1/2, suggesting potential PTPRE downstream signaling pathways. In summary, these results indicate an oncogenic role of PTPRE in chemoresistant retinoblastoma.

Chronic pain affects approximately one fifth of people worldwide and displays a huge burden for health care institutions. Some chronic pain conditions have a higher prevalence in women than men. Previous studies related these sex-specific differences to sex-hormone receptor activation and interaction with pain-related receptors like the transient receptor potential vanilloid 1 (TRPV1). Here, especially estrogen seems to play a crucial role. While the role of estrogen receptor alpha and beta in modulating TRPV1 has already been studied, the interplay of the membrane-bound and G-protein -coupled estrogen receptor (GPER1) with nociceptor-associated ion channels is still unknown. The study at hand focuses on the establishment of a human induced pluripotent stem cell (iPSC) -based nociceptor model to unravel the effect of GPER1 activation on nociceptor excitability. Therefore, a human dermal fibroblast cell line was successfully reprogrammed into the iPSC line BO-VC1 and subsequently differentiated into nociceptors expressing GPER1 besides TRPV1 and the Twik-related spinal cord potassium channel (TRESK). The activation of GPER1 by its specific agonist G-1 led to significantly reduced action potential firing rates and TRPV1-mediated calcium influx. In addition, GPER1 was found to downregulate TRPV1-mediated ion currents upon G-1 treatment in a human embryonic kidney cell -based model. Our findings support the hypothesis that GPER1 activation silences neuronal excitability in nociceptors, probably being a candidate for future research focusing on targeted pain modulation.

Secondary plant metabolites are widely used in traditional and naturopathic medicine to treat pain, infection, and inflammation. The sesquiterpenoid zerumbone, derived from the edible ginger Zingiber zerumbet , has been shown to exert analgesic, antioxidant, antitumoral, and antimicrobial effects in preclinical models, acting through multiple receptor systems including cannabinoid (CB) receptors, peroxisome proliferator-activated receptors, N-methyl-D-aspartate (NMDA) receptors, and the serotonergic system. Zerumbone also modulates inflammatory and nitric oxide–cGMP–K ⁺ ATP signaling pathways implicated in antiallodynic responses, yet its direct impact on nociceptor-associated ion channels like the Transient receptor potential vanilloid 1 (TRPV1) and the Twik-related spinal cord potassium channel (TRESK) in human cellular systems remains poorly characterized. In the present study, the antinociceptive properties of zerumbone were investigated in human HEK293-based and induced pluripotent stem cell (iPSC)-derived nociceptor models. Here, the zerumbone treatment reduced cell viability and proliferation in a concentration-dependent manner without altering TRPV1 or TRESK protein expression. Whole-cell patch-clamp recordings revealed that zerumbone reversibly inhibited TRESK-mediated outward potassium currents upon direct application, whereas bath-applied zerumbone increased outward currents, suggesting context-dependent modulation. In TRPV1-expressing HEK293 cells, SH-SY5Y neuroblastoma cells, and human iPSC-derived nociceptors, zerumbone reduced TRPV1-mediated ion currents and capsaicin-evoked calcium signals, indicating a direct or competitive inhibitory effect on TRPV1 activity. In iPSC-derived nociceptors, zerumbone decreased action potential firing at moderate depolarizing currents, shifted the resting membrane potential, and increased rheobase, consistent with reduced nociceptor excitability, while no significant changes in TRESK-mediated currents were detected. These data suggest that zerumbone attenuates human iPSC-derived nociceptor-like neuron excitability largely via TRPV1 inhibition, with a more complex, concentration- and application-method-dependent modulation of TRESK. The findings provide a mechanistic basis for the antiallodynic effects of zerumbone observed in rodent models and highlight the need for further studies in human-derived systems to clarify the precise channel-level interactions and their relevance to inflammatory and neuropathic pain.

Protein tyrosine phosphatase receptor type E (PTPRE) is a member of the “classical” protein tyrosine phosphatase subfamily and regulates a variety of cellular processes in a tissue-specific manner by antagonizing the function of protein tyrosine kinases. PTPRE plays a tumorigenic role in different human cancer cells, but its role in retinoblastoma (RB), the most common malignant eye cancer in children, remains to be elucidated. Etoposide resistant RB cell lines and RB patients display significant higher PTPRE expression levels compared to chemosensitive counterparts and the healthy human retina, respectively. PTPRE promotor methylation analyses revealed that PTPRE expression in RB is not regulated via this mechanism. Lentiviral PTPRE knockdown (KD) induced a significant decrease in growth kinetics, cell viability, and anchorage independent growth of etoposide resistant Y79 and WERI RB cells. Caspase-dependent apoptosis rates were significantly increased and a re-sensitization for etoposide could be observed after PTPRE depletion. In vivo chicken chorioallantoic membrane (CAM) assays revealed decreased tumor formation capacity as well as reduced tumor size and weight following PTPRE KD. Expression levels of miR631 were significantly downregulated in etoposide resistant RB cells and patients. Transient miR631 overexpression resulted in significantly decreased PTPRE levels and concomitantly decreased proliferation and increased apoptosis levels in etoposide resistant RB cells, impacts mirroring PTPRE KD effects and indicating PTPRE regulation via this miR. Additionally, PTPRE KD led to altered phosphorylation of protein kinase SGK3 and - dependent on the cell line - also AKT and ERK1/2, suggesting potential PTPRE downstream signaling pathways. In summary, these results indicate an oncogenic role of PTPRE in chemoresistant retinoblastoma.