Receptors, Volume 4, Issue 3 (September 2025) – 6 articles

Background/Objectives: G protein-coupled receptors (GPCRs) can promote ligand-biased signaling, yet the mechanisms that promote bias are not well understood. We have shown that C-C Chemokine Ligand 19 (CCL19) and CCL21 promote ligand-biased internalization and signaling of C-C Chemokine Receptor 7 (CCR7) in T cells. The roles of GPCR kinases (GRKs) in regulating biased CCR7 internalization and biased signaling in T cells are unclear. GRK2 is a serine/threonine kinase that phosphorylates GPCRs in response to ligand binding and is recruited to the plasma membrane via its C-terminal pleckstrin homology domain to phosphatidylinositol 4,5-bisphosphate (PIP₂). Methods: Human embryonic kidney cells (HEK293) transfected to express wild-type and mutant GRK2 and human CCR7, human T cell lines harboring heterozygous deletions of GRK2, and naïve primary T cells from GRK2 heterozygous (GRK2^+/−) or GRK2^f/f CD4-Cre mice were used to examine the effects of GRK2 on ligand-induced CCR7 signaling in T cells. We used flow cytometry to assay the effect of GRK2 on CCR7 internalization, Fluorescence Resonance Energy Transfer (FRET) to define the effect of GRK2 on CCR7 activation of Gα_i isoforms and transwell migration assays to examine the effect of GRK2 on chemotaxis. Since chemotaxis via CCR7 is mediated by phospholipase Cγ1 (PLCγ1), Western blot assays were used to measure the effect of GRK2 during downstream signaling via phosphorylation of PLCγ1. Results: We found that following CCL19 binding, GRK2 promoted kinase-dependent CCR7 recruitment of arrestin-3, rapid CCR7 internalization and Gα_i3 recruitment to CCR7. In contrast, following binding of CCL21 to CCR7, GRK2 slowed CCR7 internalization, induced recruitment of Gα_i2 to the activated receptor_, and promoted chemotaxis. Since we have shown that CCL21 promotes chemotaxis via PLCγ1, we examined the effect of GRK2 on PLCγ1 activation and found that GRK2 had no effect on CCL21-mediated PLCγ1 phosphorylation. Conclusions: GRK2 promotes differential signaling downstream of CCR7 activation by CCL19 and CCL21 and provides a model for biased signaling downstream of a GPCR driven by GRK2. Full article

Mutations in hormone receptors significantly influence infertility and the outcomes of assisted reproductive technologies (ART). This review explores the functional interplay among mutations in FSHR, LHCGR, AR, ESR1, and ESR2 hormone receptors and their combined effects on hormonal regulation, ovarian response, and implantation. Rather than analyzing receptor mutations in isolation, we explore how mutations in these genes interact within a complex hormonal signaling network, shaping reproductive outcomes. We detail the molecular mechanisms of receptor dysfunction, their associated clinical phenotypes, and the role of genetic screening in guiding personalized ART protocols. A comprehensive understanding of these interactions is crucial for optimizing treatment strategies, improving reproductive success, and advancing targeted therapeutic approaches in reproductive medicine. Full article

Boron-containing compounds (BCCs) have emerged as potential drugs. Their drug-like effects are mainly explained by their mechanisms of action in enzymes. Nowadays, some experimental data support the effects of specific BCCs on GPCRs, provided there are crystal structures that show them bound to G protein-coupled receptors (GPCRs). Some BCCs are recognized as potential ligands of GPCRs—the drug targets of many diseases. Objective: The aim of this study was to collecte up-to-date data on the interactions of BCCs with GPCRs. Methods: Data were collected from the National Center of Biotechnology Information, PubMed, Global Health, Embase, the Web of Science, and Google Scholar databases and reviewed. Results: Some experimental reports support the interactions of BCCs with several GPCRs, acting as their labels, agonists, or antagonists. These interactions can be inferred based on in silico and in vitro results if there are no available crystal structures for validating them. Conclusions: The actions of BCCs on GPCRs are no longer hypothetical, as the existing evidence supports BCCs’ interactions with and actions on GPCRs. Full article

Dictyostelium discoideum (Dicty) is a type of unicellular amoeba, but when starved, a large number of amoebas gather together to form a multicellular organism. In this review, we first introduce our cellular dynamics method for Dicty, including intracellular biochemical reactions. We then introduce a number of hidden roles of receptors revealed by our simulation studies. Of particular note is that receptor–receptor interactions are strengthened under starvation conditions, resulting in diverse dynamic functions that cannot be predicted from the action of a single receptor, such as intercellular synchronization. Furthermore, we introduce a mathematical generalization of Dicty’s receptor function and demonstrate its potential applications not only in the biological field but also in the engineering field. Full article

Skeletal muscle aging, or sarcopenia, involves progressive muscle mass and function loss, which limits mobility and independence in elderly populations. This decline is driven by chronic inflammation, oxidative stress, and insulin resistance, all of which impair muscle regeneration and accelerate protein breakdown. Mineralocorticoid receptors (MRs), known for their roles in electrolyte balance, have emerged as key regulators of these processes in skeletal muscle. MR activation promotes inflammatory signaling, increases oxidative stress, and worsens insulin resistance, accelerating sarcopenia progression. This review examines the impact of MRs on muscle health and highlights the therapeutic potential of targeting these receptors to counteract age-related muscle loss. MR antagonists, such as spironolactone, show promise in reducing inflammation and oxidative damage, potentially slowing sarcopenia. Physical exercise, an established intervention for muscle health, may enhance MR antagonism effects by improving insulin sensitivity and reducing inflammation. However, more research is needed to determine the efficacy and safety of combined MR antagonists and exercise protocols for preventing sarcopenia in older adults. Full article

Background: The development of cerebral organoids created from human pluripotent stem cells in 3D culture may greatly improve the discovery of neuropsychiatric medicines. Methods: In the current study we differentiated neural organoids from a human pluripotent stem cell line in vitro, recorded the development of neurophysiological activity using multielectrode arrays (MEAs) and characterized the neuropharmacology of synaptic signaling over 8 months in vitro. In addition, we investigated the ability of these organoids to display epileptiform activity in response to a convulsant agent and the effects of antiseizure medicines to inhibit this abnormal activity. Results: Single and bursts of action potentials from individual neurons and network bursts were recorded on the MEA plates and significantly increased and became more complex from week 7 to week 30, consistent with neural network formation. Neural spiking was reduced by the Na channel blocker tetrodotoxin but increased by the inhibitor of K_V7 potassium channels XE991, confirming the involvement of voltage-gated sodium and potassium channels in action potential activity. The GABA antagonists bicuculline and picrotoxin each increased the spike rate, consistent with inhibitory synaptic signaling. In contrast, the glutamate receptor antagonist kynurenic acid inhibited the spike rate, consistent with excitatory synaptic transmission in the organoids. The convulsant 4-aminopyridine increased spiking, bursts and synchronized firing, consistent with epileptiform activity in vitro. The anticonvulsants carbamazepine, ethosuximide and diazepam each inhibited this epileptiform neural activity. Conclusions: Together, our data demonstrate that neural organoids form inhibitory and excitatory synaptic circuits, generate epileptiform activity in response to a convulsant agent and detect the antiseizure properties of diverse antiepileptic drugs, supporting their value in drug discovery. Full article