Receptors of the Class Frizzled (FZD, nomenclature as agreed by the NC-IUPHAR subcommittee on the Class Frizzled GPCRs [184]), are GPCRs highly conserved across species and were originally identified in Drosophila [21]. While SMO shows structural resemblance to the 10 FZDs, it is functionally separated as it is involved in Hedgehog signaling [184]. SMO exerts its effects by activating heterotrimeric G proteins or stabilization of GLI by sequestering catalytic PKA subunits [191, 6, 62]. While SMO itself is bound by sterols and oxysterols [28, 96], FZDs are activated by WNTs, which are cysteine-rich lipoglycoproteins with fundamental functions in ontogeny and tissue homeostasis. FZD signaling was initially divided into two pathways, being either dependent on the accumulation of the transcription regulator β-catenin or being β-catenin-independent (often referred to as canonical vs. non-canonical WNT/FZD signaling, respectively). Nevertheless, it makes pharmacologically more sense to define downstream signaling by transducer coupling to either DVL or heterotrimeric G proteins [185]. WNT stimulation of FZDs can, in cooperation with the low density lipoprotein receptors LRP5 (O75197) and LRP6 (O75581), lead to the inhibition of a constitutively active destruction complex, which results in the accumulation of β-catenin and subsequently its translocation to the nucleus. β-catenin, in turn, modifies gene transcription by interacting with TCF/LEF transcription factors. WNT/β-catenin-dependent signalling can also be activated by FZD subtype-specific WNT surrogates [142]. β-catenin-independent FZD signalling is far more complex with regard to the diversity of the activated pathways. WNT/FZD signalling can lead to the activation of heterotrimeric G proteins [35, 188, 159], the elevation of intracellular calcium [194], activation of cGMP-specific PDE6 [2] and elevation of cAMP as well as RAC-1, JNK, Rho and Rho kinase signalling [61]. Novel resonance energy transfer-based tools have allowed the study of the GPCR-like nature of FZDs in greater detail. Upon ligand stimulation, FZDs undergo conformational changes and signal via heterotrimeric G proteins [248, 249, 110, 183, 108, 56, 13]. Furthermore, the phosphoprotein Dishevelled constitutes a key transducer in WNT/FZD signaling towards planar-cell-polarity-like pathways. Importantly, FZDs adopt distinct conformational landscapes that regulate pathway selection [249, 54]. As with other GPCRs, members of the Frizzled family are functionally dependent on the arrestin scaffolding protein for internalization [24], as well as for β-catenin-dependent [15] and -independent [93, 16] signalling. The pattern of cell signalling is complicated by the presence of additional ligands, which can enhance or inhibit FZD signalling (secreted Frizzled-related proteins (sFRP), Wnt-inhibitory factor (WIF), sclerostin or Dickkopf (DKK)), as well as modulatory (co)-receptors with Ryk, ROR1, ROR2 and PTK7, which may also function as independent signaling proteins. An important FZD4-selective non-WNT agonist is the norrin cysteine knot protein, which is a key player in FZD4-mediated vascularization for example in the retina and which is functionally related to familial exudative vitreoretinopathy (FEVR).

Lactate was long considered a byproduct of glycolysis and associated with various harmful effects. However, the role of lactate was expanded with the finding that it also can act as a signaling molecule through the G protein–coupled receptor Hydroxycarboxylic Acid Receptor 1 (HCAR1). The receptor was shown to be primarily expressed in adipocytes but is also expressed in many other tissues and cell types. Activation of HCAR1 can help regulate lipolysis and improve insulin sensitivity, making it a promising target for managing obesity and other metabolic disorders. While HCAR1 activation offers therapeutic benefits for metabolic diseases, it can also promote cancer cell survival and metastasis, necessitating a nuanced approach to avoid unintended tumor growth. However, only a few ligands have been reported for HCAR1, and their signaling pathways remain unexplored. Using enhanced bystander bioluminescence resonance energy transfer (ebBRET) to study G protein activation and β-arrestin recruitment following ligand addition, we were able to identify compounds such as AZ7136, a potent HCAR1 agonist, AZ2114 a partial agonist, and establish GPR81 agonist 1 as an ago-positive allosteric modulator. We also show that HCAR1 preferentially activates the Gαi/o and Gαs pathways without recruiting β-arrestins. These findings enhance our understanding of the signaling profile of HCAR1 and the newly characterized ligands could be used as molecular tools to understand more about HCAR1 in metabolic disease. One Sentence Summary This study used the ebBRET platform to identify and characterize several synthetic ligands for the lactate receptor HCAR1, significantly advancing our understanding of HCAR1 signaling. ### Competing Interest Statement M.B. is the president of the scientific advisory board for Domain Therapeutics. Some of the biosensors used in this study were patented and licensed to Domain Therapeutics. All biosensors are available for academic research through a regular material transfer agreement. The other authors declare that they have no competing interests. Swedish Society for Medical Research, , PG-22-0405-H-01, PD20-0153, SG-24-0176-B, S19-0121 Stiftelsen Konung Gustaf V:s 80-årsfond, , FAI-2023-0985 Novo Nordisk Foundation, https://ror.org/04txyc737, NNF24SA0094137 Jeansson Foundations, https://ror.org/00r6p8t42, Karolinska Institutet, https://ror.org/056d84691, CIHR, , PJT-183758 NSERC, , RGPIN-2019-05556 Ragnar Söderberg Foundation, https://ror.org/03f1pm042, 7/22-A Swedish Foundation for Strategic Research, https://ror.org/044wr7g58, FFL18-0182 Knut and Alice Wallenberg Foundation, https://ror.org/004hzzk67, 2021.0065 Swedish Research Council, https://ror.org/03zttf063, 2019-01891

Biased agonism of G protein-coupled receptors (GPCRs) offers potential for safer medications. Current efforts have explored the balance between G proteins and β-arrestin; however, other transducers like GPCR kinases (GRKs) remain understudied. GRK2 is essential for β2 adrenergic receptor (β2AR)-mediated glucose uptake, but β2AR agonists are considered poor clinical candidates for glycemic management due to Gs/cyclic AMP (cAMP)-induced cardiac side effects and β-arrestin-dependent desensitization. Using ligand-based virtual screening and chemical evolution, we developed pathway-selective agonists of β2AR that prefer GRK coupling. These compounds perform well in preclinical models of hyperglycemia and obesity and demonstrate a lower potential for cardiac and muscular side effects compared with standard β2-receptor agonists and incretin mimetics, respectively. Furthermore, the lead candidate showed favorable pharmacokinetics and was well tolerated in a placebo-controlled clinical trial. GRK-biased β2AR partial agonists are thus promising oral alternatives to injectable incretin mimetics used in the treatment of type 2 diabetes and obesity.

Objective: Physical activity promotes health, whereas inactivity is associated with metabolic impairment. The transcription factor nuclear receptor subfamily 4 group A member 3 (NR4A3) is a pleiotropic regulator of skeletal muscle exercise adaptation and metabolism. However, the consequence of lower NR4A3 expression remains largely unexplored. We investigated the impact of NR4A3 downregulation on human skeletal muscle metabolism. Methods: Published transcriptomic datasets from human bed rest and limb immobilisation studies were curated to meta-analyse the effect of physical inactivity on skeletal muscle NR4A3 levels. In primary human skeletal myotubes, siRNA and lentivirus were used to silence and overexpress NR4A3, respectively. Basal and stimulated (insulin ± leucine) signal transduction was determined by immunoblot analysis. Effects on glucose, fatty acid, and protein metabolism were measured using radiolabelled substrate assays. Lactate production was assessed in culture supernatant by colourimetry. Cell morphology was analysed by immunocytochemistry and gene expression was quantified by RT-qPCR. Results: Physical inactivity decreased skeletal muscle NR4A3 (−27%), concomitant with pathways related to mitochondrial function, cytoskeleton organization, chromatin regulation, protein synthesis and degradation. Silencing of NR4A3 reduced glucose oxidation (−18%) and increased lactate production (+23%) in vitro. This coincided with greater signalling downstream of AMPK and elevated rates of basal (+26%) and FCCP-stimulated (+55%) fatty acid oxidation. NR4A3 downregulation lowered protein synthesis (−25%), and impaired mTORC1 signalling and ribosomal transcription. Alternatively, overexpression of the canonical NR4A3 protein isoform (+290%) augmented translation and total cellular protein content, which protected myotubes against dexamethasone-induced atrophy. Moreover, partial restoration of NR4A3 levels rescued glucose oxidation in NR4A3-silenced muscle cells and restored phosphorylation of mTORC1 substrates. NR4A3 depletion reduced myotube area (−48%) and further altered protein and gene expression of key contractile elements in skeletal muscle. Conclusions: Our study connects reduced NR4A3 expression with physical inactivity and indicates that NR4A3 downregulation in human skeletal muscle has adverse effects on glucose metabolism and protein synthesis. Thus, decrements in NR4A3 abundance could be causal in the deleterious health consequences resulting from sedentary lifestyles and targeting NR4A3 may offer new avenues for combating conditions such as disuse muscle atrophy.

In light of the success of blockbuster drugs for type 2 diabetes and obesity based on the GLP-1 hormone, drugmakers have concentrated their efforts on developing new and improved variations that address the route of administration, dosing, pathway selectivity, or polypharmacology. While some of these modifications have demonstrated improved efficacy in clinical studies and offered exciting opportunities for treating other diseases, drug-induced shifts to the conformational landscape of target receptors may have consequences for side effects. Our review summarizes advances in the understanding of the biochemistry, pharmacogenomics, and molecular pharmacology of incretins and their cognate receptors. We further highlight the current landscape of incretin mimetics and discuss how differences in compartmentalized pathway selectivity affect drug action and outcomes.

Climate change and population densities accelerated transmission of highly pathogenic viruses to humans, including the Crimean-Congo haemorrhagic fever virus (CCHFV). Here we report that the Low Density Lipoprotein Receptor (LDLR) is a critical receptor for CCHFV cell entry, playing a vital role in CCHFV infection in cell culture and blood vessel organoids. The interaction between CCHFV and LDLR is highly specific, with other members of the LDLR protein family failing to bind to or neutralize the virus. Biosensor experiments demonstrate that LDLR specifically binds the surface glycoproteins of CCHFV. Importantly, mice lacking LDLR exhibit a delay in CCHFV-induced disease. Furthermore, we identified the presence of Apolipoprotein E (ApoE) on CCHFV particles. Our findings highlight the essential role of LDLR in CCHFV infection, irrespective of ApoE presence, when the virus is produced in tick cells. This discovery holds profound implications for the development of future therapies against CCHFV.

ObjectiveSimultaneous activation of β2- and β3-adrenoceptors (ARs) improves whole-body metabolism via beneficial effects in skeletal muscle and brown adipose tissue (BAT). Nevertheless, high-efficacy agonists simultaneously targeting these receptors whilst limiting activation of β1-ARs – and thus inducing cardiovascular complications – are currently non-existent. Therefore, we here developed and evaluated the therapeutic potential of a novel β2- and β3-AR, named ATR-127, for the treatment of obesity and its associated metabolic perturbations in preclinical models.MethodsIn the developmental phase, we assessed the impact of ATR-127's on cAMP accumulation in relation to the non-selective β-AR agonist isoprenaline across various rodent β-AR subtypes, including neonatal rat cardiomyocytes. Following these experiments, L6 muscle cells were stimulated with ATR-127 to assess the impact on GLUT4-mediated glucose uptake and intramyocellular cAMP accumulation. Additionally, in vitro, and in vivo assessments are conducted to measure ATR-127's effects on BAT glucose uptake and thermogenesis. Finally, diet-induced obese mice were treated with 5mg/Kg ATR-127 for 21 days to investigate the effects on glucose homeostasis, body weight, fat mass, skeletal muscle glucose uptake, BAT thermogenesis and hepatic steatosis.ResultsExposure of L6 muscle cells to ATR-127 robustly enhanced GLUT4-mediated glucose uptake despite low intramyocellular cAMP accumulation. Similarly, ATR-127 markedly increased BAT glucose uptake and thermogenesis both in vitro and in vivo. Prolonged treatment of diet-induced obese mice with ATR-127 dramatically improved glucose homeostasis, an effect accompanied by decreases in body weight and fat mass. These effects were paralleled by an enhanced skeletal muscle glucose uptake, BAT thermogenesis, and improvements in hepatic steatosis.ConclusionsOur results demonstrate that ATR-127 is a highly effective, novel β2- and β3-ARs agonist holding great therapeutic promise for the treatment of obesity and its comorbidities, whilst potentially limiting cardiovascular complications. As such, the therapeutic effects of ATR-127 should be investigated in more detail in clinical studies.

Background and Purpose The gut hormone glucose-dependent insulinotropic polypeptide (GIP) signals via the GIP receptor (GIPR) resulting in postprandial processes such as potentiation of glucose-stimulated insulin secretion. Translation of results from rodent to human studies has, however, been challenged by contradictive therapeutic effects of GIPR-targeting compounds. We, therefore, investigated the variation between species focusing on GIPR desensitization and the role of the C-terminus. Experimental Approach Species variants of the GIPR were studied in vitro for endogenous ligand affinity, G protein activation (cAMP accumulation), recruitment of beta-arrestin, and internalization. Variants of the mouse, rat, and human GIPRs with swapped C-terminal tails were studied in parallel. Key Results The human GIPR is more prone to internalization than rodent GIPRs. Despite similar agonist affinities and potencies for G-activation especially the mouse GIPR has a reduced receptor desensitization, internalization, and beta-arrestin recruitment. Using an enzyme-stable, long-acting GIP analogue, the species differences were even more pronounced. “Tail swapped” human, rat, and mouse GIPRs were all fully functional in their G-coupling and the mouse GIPR regained internalization and beta-arrestin 2-recruitment properties with the human tail while the human GIPR lost the ability to recruit beta-arrestin 2 when its own C-terminus was replaced by the rat or mouse tail. Conclusion and Implications Desensitization of the human GIPR is dependent on the C-terminal tail. The diverse functionality of the C-terminal tail as well as receptor internalization patterns between species, especially human and mouse GIPRs, are important factors that could influence the preclinical therapeutic evaluation of GIPR targeting compounds.

G protein–coupled receptors (GPCRs) regulate cellular signaling processes by coupling to diverse combinations of heterotrimeric G proteins composed of Gα, Gβ, and Gγ subunits. Biosensors based on bioluminescence resonance energy transfer (BRET) have advanced our understanding of GPCR functional selectivity. Some BRET biosensors monitor ligand-induced conformational changes in the receptor or G proteins, whereas others monitor the recruitment of downstream effectors to sites of G protein activation. Here, we compared the ability of conformation-and activation-based BRET biosensors to assess the coupling of various class A and B GPCRs to specific Gα proteins in cultured cells. These GPCRs included serotonin 5-HT 2A and 5-HT 7 receptors, the GLP-1 receptor (GLP-1R), and the M 3 muscarinic receptor. We observed different signaling profiles between the two types of sensors, highlighting how data interpretation could be affected by the nature of the biosensor. We also found that the identity of the Gβγ subunits used in the assay could differentially influence the selectivity of a receptor toward Gα subtypes, emphasizing the importance of the receptor-Gβγ pairing in determining Gα coupling specificity. Last, the addition of epitope tags to the receptor could affect stoichiometry and coupling selectivity and yield artifactual findings. These results highlight the need for careful sensor selection and experimental design when probing GPCR–G protein coupling.

Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of chronic liver disease with few therapeutic options. To narrow the translational gap in the development of pharmacological MASH treatments, a 3D liver model from primary human hepatocytes and non-parenchymal cells derived from patients with histologically confirmed MASH was established. The model closely mirrors disease-relevant endpoints, such as steatosis, inflammation and fibrosis, and multi-omics analyses show excellent alignment with biopsy data from 306 MASH patients and 77 controls. By combining high-content imaging with scalable biochemical assays and chemogenomic screening, multiple novel targets with anti-steatotic, anti-inflammatory, and anti-fibrotic effects are identified. Among these, activation of the muscarinic M1 receptor (CHRM1) and inhibition of the TRPM8 cation channel result in strong anti-fibrotic effects, which are confirmed using orthogonal genetic assays. Strikingly, using biosensors based on bioluminescence resonance energy transfer, a functional interaction along a novel MASH signaling axis in which CHRM1 inhibits TRPM8 via Gq/11 and phospholipase C-mediated depletion of phosphatidylinositol 4,5-bisphosphate can be demonstrated. Combined, this study presents the first patient-derived 3D MASH model, identifies a novel signaling module with anti-fibrotic effects, and highlights the potential of organotypic culture systems for phenotype-based chemogenomic drug target identification at scale.

Several viruses hijack various forms of endocytosis in order to infect host cells. Here, we report the discovery of a molecule with antiviral properties that we named virapinib, which limits viral entry by macropinocytosis. The identification of virapinib derives from a chemical screen using high-throughput microscopy, where we identified chemical entities capable of preventing infection with a pseudotype virus expressing the spike (S) protein from SARS-CoV-2. Subsequent experiments confirmed the capacity of virapinib to inhibit infection by SARS-CoV-2, as well as by additional viruses, such as mpox virus and TBEV. Mechanistic analyses revealed that the compound inhibited macropinocytosis, limiting this entry route for the viruses. Importantly, virapinib has no significant toxicity to host cells. In summary, we present the discovery of a molecule that inhibits macropinocytosis, thereby limiting the infectivity of viruses that use this entry route such as SARS-CoV2.

The transcription factor NR4A3 is regulated by exercise and a potent modulator of skeletal muscle metabolism. We report here that physical inactivity decreased skeletal muscle NR4A3 levels, concomitant with mitochondrial function and proteostasis pathways. Silencing of NR4A3 in myotubes decreased glucose oxidation and increased lactate production. This coincided with greater signalling downstream of AMPK and elevated rates of fatty acid oxidation. While NR4A3 silencing reduced protein synthesis, mTORC1 signalling, and ribosomal transcription, overexpression of the canonical NR4A3 protein isoform augmented translation and cellular protein content. Moreover, restoration of NR4A3 levels rescued glucose oxidation in NR4A3-silenced myotubes and restored phosphorylation of mTORC1 substrates. NR4A3 depletion reduced myotube area and altered the abundance of contractile elements. Thus, downregulation of NR4A3 has adverse effects on skeletal muscle metabolism, myotube size, and contractile apparatus by directing mTORC1 signalling and ribosomal biogenesis. Our data demonstrate that NR4A3 controls skeletal muscle atrophy associated with physical inactivity.

Incretin-based therapies are highly successful in combatting obesity and type 2 diabetes(1). Yet both activation and inhibition of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in combination with glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) activation have resulted in similar clinical outcomes, as demonstrated by the GIPR-GLP-1R co-agonist tirzepatide(2) and AMG-133 (ref. (3)) combining GIPR antagonism with GLP-1R agonism. This underlines the importance of a better understanding of the GIP system. Here we show the necessity of beta-arrestin recruitment for GIPR function, by combining in vitro pharmacological characterization of 47 GIPR variants with burden testing of clinical phenotypes and in vivo studies. Burden testing of variants with distinct ligand-binding capacity, Gs activation (cyclic adenosine monophosphate production) and beta-arrestin 2 recruitment and internalization shows that unlike variants solely impaired in Gs signalling, variants impaired in both Gs and beta-arrestin 2 recruitment contribute to lower adiposity-related traits. Endosomal Gs-mediated signalling of the variants shows a beta-arrestin dependency and genetic ablation of beta-arrestin 2 impairs cyclic adenosine monophosphate production and decreases GIP efficacy on glucose control in male mice. This study highlights a crucial impact of beta-arrestins in regulating GIPR signalling and overall preservation of biological activity that may facilitate new developments in therapeutic targeting of the GIPR system.

Shane C. Wright1,2,3 and Volker M. Lauschke1,4,5 1Department of Physiology & Pharmacology, Karolinska Institutet, Stockholm, Sweden 2Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC, Canada 3Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada 4Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany 5University of Tübingen, Tübingen, Germany

Species richness has been found to increase from the poles to the tropics but with a small dip near the equator over all marine fishes. Phylogenetic diversity measures offer an alternative perspective on biodiversity linked to evolutionary history. If phylogenetic diversity is standardized for species richness, then it may indicate places with relatively high genetic diversity. Latitudes and depths with both high species and phylogenetic diversity would be a priority for conservation. We compared latitudinal and depth gradients of species richness, and three measures of phylogenetic diversity, namely average phylogenetic diversity (AvPD), the sum of the higher taxonomic levels (STL) and the sum of the higher taxonomic levels divided by the number of species (STL/spp) for modelled ranges of 5,619 marine fish species. We distinguished all, bony and cartilaginous fish groups and four depth zones namely: whole water column; 0 –200 m; 201–1,000 m; and 1,001–6,000 m; at 5° latitudinal intervals from 75°S to 75°N, and at 100 m depth intervals from 0 m to 3,500 m. Species richness and higher taxonomic richness (STL) were higher in the tropics and subtropics with a small dip at the equator, and were significantly correlated among fish groups and depth zones. Species assemblages had closer phylogenetic relationships (lower AvPD and STL/spp) in warmer (low latitudes and shallow water) than colder environments (high latitudes and deep sea). This supports the hypothesis that warmer shallow latitudes and depths have had higher rates of evolution across a range of higher taxa. We also found distinct assemblages of species in different depth zones such that deeper sea species are not simply a subset of shallow assemblages. Thus, conservation needs to be representative of all latitudes and depth zones to encompass global biodiversity.

G protein-coupled receptors are important drug targets that engage and activate signaling transducers in multiple cellular compartments. Delineating therapeutic signaling from signaling associated with adverse events is an important step towards rational drug design. The glucagon-like peptide-1 receptor (GLP-1R) is a validated target for the treatment of diabetes and obesity, but drugs that target this receptor are a frequent cause of adverse events. Using recently developed biosensors, we explored the ability of GLP-1R to activate 15 pathways in 4 cellular compartments and demonstrate that modifications aimed at improving the therapeutic potential of GLP-1R agonists greatly influence compound efficacy, potency, and safety in a pathway- and compartment-selective manner. These findings, together with comparative structure analysis, time-lapse microscopy, and phosphoproteomics, reveal unique signaling signatures for GLP-1R agonists at the level of receptor conformation, functional selectivity, and location bias, thus associating signaling neighborhoods with functionally distinct cellular outcomes and clinical consequences.

Receptors of the Class Frizzled (FZD, nomenclature as agreed by the NC-IUPHAR subcommittee on the Class Frizzled GPCRs [180]), are GPCRs originally identified in Drosophila [20], which are highly conserved across species. While SMO shows structural resemblance to the 10 FZDs, it is functionally separated as it is involved in the Hedgehog signaling pathway [180]. SMO exerts its effects by activating heterotrimeric G proteins or stabilization of GLI by sequestering catalytic PKA subunits [186, 6, 58]. While SMO itself is bound by sterols and oxysterols [27, 94], FZDs are activated by WNTs, which are cysteine-rich lipoglycoproteins with fundamental functions in ontogeny and tissue homeostasis. FZD signalling was initially divided into two pathways, being either dependent on the accumulation of the transcription regulator β-catenin or being β-catenin-independent (often referred to as canonical vs. non-canonical WNT/FZD signalling, respectively). WNT stimulation of FZDs can, in cooperation with the low density lipoprotein receptors LRP5 (O75197) and LRP6 (O75581), lead to the inhibition of a constitutively active destruction complex, which results in the accumulation of β-catenin and subsequently its translocation to the nucleus. β-catenin, in turn, modifies gene transcription by interacting with TCF/LEF transcription factors. WNT/β-catenin-dependent signalling can also be activated by FZD subtype-specific WNT surrogates [138]. β-catenin-independent FZD signalling is far more complex with regard to the diversity of the activated pathways. WNT/FZD signalling can lead to the activation of heterotrimeric G proteins [34, 183, 155], the elevation of intracellular calcium [189], activation of cGMP-specific PDE6 [2] and elevation of cAMP as well as RAC-1, JNK, Rho and Rho kinase signalling [57]. Novel resonance energy transfer-based tools have allowed the study of the GPCR-like nature of FZDs in greater detail. Upon ligand stimulation, FZDs undergo conformational changes and signal via heterotrimeric G proteins [244, 245, 107, 179, 104]. Furthermore, the phosphoprotein Dishevelled constitutes a key player in WNT/FZD signalling towards planar-cell-polarity-like pathways. Importantly, FZDs exist in at least two distinct conformational states that regulate pathway selection [245]. As with other GPCRs, members of the Frizzled family are functionally dependent on the arrestin scaffolding protein for internalization [23], as well as for β-catenin-dependent [14] and -independent [91, 15] signalling. The pattern of cell signalling is complicated by the presence of additional ligands, which can enhance or inhibit FZD signalling (secreted Frizzled-related proteins (sFRP), Wnt-inhibitory factor (WIF), sclerostin or Dickkopf (DKK)), as well as modulatory (co)-receptors with Ryk, ROR1, ROR2 and Kremen, which may also function as independent signalling proteins.

Abstract Receptors of the Class Frizzled (FZD, nomenclature as agreed by the nomenclature as agreed by the NC-IUPHARNC-IUPHAR subcommittee on the subcommittee on the Class Frizzled GPCRs [ Class Frizzled GPCRs [180180]] ), are GPCRs originally identified in Drosophila [20], which are highly conserved across species. While SMO shows structural resemblance to the 10 FZDs, it is functionally separated as it is involved in the Hedgehog signaling pathway [180]. SMO exerts its effects by activating heterotrimeric G proteins or stabilization of GLI by sequestering catalytic PKA subunits [186, 6, 58]. While SMO itself is bound by sterols and oxysterols [27, 94], FZDs are activated by WNTs, which are cysteine-rich lipoglycoproteins with fundamental functions in ontogeny and tissue homeostasis. FZD signalling was initially divided into two pathways, being either dependent on the accumulation of the transcription regulator β-catenin or being β-catenin-independent (often referred to as canonical vs. non-canonical WNT/FZD signalling, respectively). WNT stimulation of FZDs can, in cooperation with the low density lipoprotein receptors LRP5 (O75197) and LRP6 (

Divaricate plant species account for more than 10% of New Zealand/Aotearoa's woody flora, a higher proportion for that life form than anywhere else on earth. Two main hypotheses have been proposed to account for the prevalence of this phenotype. The first suggests herbivorous birds, particularly large flightless moa, exerted selective pressure on many plants to adopt the form. The second proposes climate as the main driver since insular New Zealand has many exposed habitats and, historically, experienced stressing conditions during the Pleistocene. Our study investigated two questions to shed further light on the evolution of divaricates, in particular related to the potential influence of browsing by large avian herbivores. First, divaricate plants have been posited to have a higher tensile strength than non-divaricates as a defence mechanism against moa browsing. We tested the great majority of New Zealand plant genera within which divaricates occur, contrasting the stem tensile strength of these plants against their closest non-divaricate counterparts using accurate testing technology. The results indicate divaricate species have tensile strength that approaches twice that of non-divaricates across a broad and disparate phylogenetic range that includes gymnosperms and many clades of angiosperms. Second, we tested the species level distributions of widely dispersed woody plant genera across the New Zealand archipelago on islands where moa had been present or always absent. We found that no endemic divaricate species occurred on any islands from which moa had been permanently absent. In contrast, their non-divaricate counterparts were commonly endemic to those same islands.

We recently proposed restoration of indigenous names within scientific nomenclature and briefly outlined how the taxonomic codes could be amended to accommodate this within the Linnaean classification system. Our proposal included a process whereby Indigenous Peoples could submit long-established indigenous names to replace current names under a modified International Code of Nomenclature for algae, fungi, and plants (ICN). Here we expand on this proposal with specific recommendations for changes to the ICN.