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1.
The expanding roles and mechanisms of G protein-mediated presynaptic inhibition.
Zurawski, Z, Yim, YY, Alford, S, Hamm, HE
The Journal of biological chemistry. 2019;(5):1661-1670
Abstract
Throughout the past five decades, tremendous advancements have been made in our understanding of G protein signaling and presynaptic inhibition, many of which were published in the Journal of Biological Chemistry under the tenure of Herb Tabor as Editor-in-Chief. Here, we identify these critical advances, including the formulation of the ternary complex model of G protein-coupled receptor signaling and the discovery of Gβγ as a critical signaling component of the heterotrimeric G protein, along with the nature of presynaptic inhibition and its physiological role. We provide an overview for the discovery and physiological relevance of the two known Gβγ-mediated mechanisms for presynaptic inhibition: first, the action of Gβγ on voltage-gated calcium channels to inhibit calcium influx to the presynaptic active zone and, second, the direct binding of Gβγ to the SNARE complex to displace synaptotagmin downstream of calcium entry, which has been demonstrated to be important in neurons and secretory cells. These two mechanisms act in tandem with each other in a synergistic manner to provide more complete spatiotemporal control over neurotransmitter release.
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2.
A low-fat diet up-regulates expression of fatty acid taste receptor gene FFAR4 in fungiform papillae in humans: a co-twin randomised controlled trial.
Costanzo, A, Liu, D, Nowson, C, Duesing, K, Archer, N, Bowe, S, Keast, R
The British journal of nutrition. 2019;(11):1212-1220
Abstract
Fatty acid taste (FAT) perception is involved in the regulation of dietary fat intake, where impaired FAT is associated with increased fatty food intake. There are a number of FAT receptors identified on human taste cells that are potentially responsible for FAT perception. Manipulating dietary fat intake, and in turn FAT perception, would elucidate the receptors that are associated with long-term regulation of FAT perception. The present study aimed to assess associations between diet-mediated changes to FAT receptors and FAT perception in humans. A co-twin randomised controlled trial was conducted, where each matching twin within a pair were randomly allocated to either an 8-week low-fat (LF; <20 % energy fat) or an 8-week high-fat (HF; >35 % energy fat) diet. At baseline and week 8, fungiform papillae were biopsied in the fasted state and FAT receptor gene expressions (cluster of differentiation 36 (CD36), free fatty acid receptor 2 (FFAR2), FFAR4, G protein-coupled receptor 84 (GPR84) and a delayed rectifying K+ channel (K+ voltage-gated channel subfamily A member 2; KCNA2)) were measured using RT-PCR; and FAT threshold (FATT) was assessed using three-alternate forced choice methodology. Linear mixed models were fitted, adjusting for correlation between co-twins. Intake was compliant with the study design, with the LF and HF groups consuming 14·8 and 39·9 % energy from fat, respectively. Expression of FFAR4 increased by 38 % in the LF group (P = 0·023; time-diet interaction P = 0·063). ΔFFAR4 (Δ, week 8-baseline) was associated with Δfat intake (g) ( = -159·4; P < 0·001) and ΔFATT ( = -8·8; P = 0·016). In summary, FFAR4 is involved in long-term diet-mediated changes to FAT perception. Manipulating dietary fat intake, and therefore FFAR4 expression, might aid in reducing taste-mediated passive overconsumption of fatty foods.
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3.
G protein-coupled receptor 119 agonist DS-8500a effects on pancreatic β-cells in Japanese type 2 diabetes mellitus patients.
Watada, H, Shiramoto, M, Irie, S, Terauchi, Y, Yamada, Y, Shiosakai, K, Myobatake, Y, Taguchi, T
Journal of diabetes investigation. 2019;(1):84-93
Abstract
AIMS/INTRODUCTION Pancreatic β-cell dysfunction contributes to type 2 diabetes mellitus progression. Drugs that improve insulin secretion might be a valuable treatment approach. The present study aimed to evaluate the effect of the G protein-coupled receptor 119 agonist DS-8500a on insulin secretory capacity in Japanese type 2 diabetes mellitus patients. MATERIALS AND METHODS This single-center, 4-week, randomized, double-blind, cross-over study enrolled 21 Japanese drug-naïve type 2 diabetes mellitus patients aged ≥20 years with glycated hemoglobin ≥7.0 and <9.0% (NCT02669732, JapicCTI 163126). Patients received 75 mg of DS-8500a or a placebo orally daily for 4 weeks in a random order. A combined euglycemic-hyperinsulinemic and hyperglycemic clamp test was carried out to assess insulin secretion and insulin sensitivity before and after each 4-week treatment period. Primary end-points were first-phase insulin secretion (insulin area under the curve [AUC]180-190 min and C-peptide AUC180-190 min during the clamp test) and second-phase insulin secretion (insulin AUC190-300 min and C-peptide AUC190-300 min ). Insulin sensitivity (M and M/I values), disposition index and changes in lipid profile were also assessed. RESULTS DS-8500a significantly increased first- and second-phase insulin AUC (P = 0.0011, P = 0.0112) and C-peptide AUC (P = 0.0012, P < 0.0001) compared with the placebo. At day 28, M and M/I values were comparable with those of the placebo, whereas the disposition index for insulin and C-peptide was significantly increased (P = 0.0108, P = 0.0002). Total cholesterol, low-density lipoprotein cholesterol and triglyceride concentrations were significantly reduced, and high-density lipoprotein cholesterol concentrations were significantly increased compared with the placebo. No significant treatment-emergent adverse events occurred. CONCLUSION DS-8500a enhanced insulin secretory capacity, but not insulin sensitivity.
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4.
Taste, olfactory and texture related genes and food choices: implications on health status.
Precone, V, Beccari, T, Stuppia, L, Baglivo, M, Paolacci, S, Manara, E, Miggiano, GAD, Falsini, B, Trifirò, A, Zanlari, A, et al
European review for medical and pharmacological sciences. 2019;(3):1305-1321
Abstract
OBJECTIVE The food choices are due to a mixture of sensory signals including gustatory, olfactory, and texture sensations. The aim of this quality review was to update data about studies concerning genetics of taste, olfactory and texture receptors and their influence on the health status in humans. MATERIALS AND METHODS An electronic search was conducted in MEDLINE, Pubmed database and Scopus, for articles published in English until December 2018. Two independent researches selected the studies and extracted the data. RESULTS The review confirms the importance of inter-individual variations in taste, olfactory and texture related genes on food choices and their implications in the susceptibility to nutrition-related conditions such as obesity, dental caries, diabetes, cardiovascular disease, hypertension, hyperlipidemia and cancer. CONCLUSIONS The knowledge of variants in taste, olfactory and texture related genes can contribute to the prevention of diseases related to unhealthy nutrition. Further studies would be useful to identify other variants in the genes involved in these systems.
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5.
TAS2R38 bitter taste receptor and attainment of exceptional longevity.
Melis, M, Errigo, A, Crnjar, R, Pes, GM, Tomassini Barbarossa, I
Scientific reports. 2019;(1):18047
Abstract
Bitter taste receptors play crucial roles in detecting bitter compounds not only in the oral cavity, but also in extraoral tissues where they are involved in a variety of non‒tasting physiological processes. On the other hand, disorders or modifications in the sensitivity or expression of these extraoral receptors can affect physiological functions. Here we evaluated the role of the bitter receptor TAS2R38 in attainment of longevity, since it has been widely associated with individual differences in taste perception, food preferences, diet, nutrition, immune responses and pathophysiological mechanisms. Differences in genotype distribution and haplotype frequency at the TAS2R38 gene between a cohort of centenarian and near-centenarian subjects and two control cohorts were determined. Results show in the centenarian cohort an increased frequency of subjects carrying the homozygous genotype for the functional variant of TAS2R38 (PAV/PAV) and a decreased frequency of those having homozygous genotype for the non-functional form (AVI/AVI), as compared to those determined in the two control cohorts. In conclusion, our data providing evidence of an association between genetic variants of TAS2R38 gene and human longevity, suggest that TAS2R38 bitter receptor can be involved in the molecular physiological mechanisms implied in the biological process of aging.
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6.
Effect of DS-8500a, a Novel G Protein-Coupled Receptor 119 Agonist, on the Pharmacokinetics of Rosuvastatin and Atorvastatin in Healthy Subjects.
Maekawa, Y, Furuie, H, Kato, M, Myobatake, Y, Kamiyama, E, Watanabe, A, Shiosakai, K, Taguchi, T, Bass, R, Zhou, J, et al
Clinical drug investigation. 2019;(10):967-978
Abstract
BACKGROUND Non-clinical study data suggest that DS-8500a, a G protein-coupled receptor 119 agonist, exhibits antidiabetic activity, inhibition of some transporters and induction of cytochrome P450 (CYP) 3A. Statins are substrates for some transporters and CYP3A that may be coadministered with DS-8500a in clinical practice. OBJECTIVE To determine the potential effects of DS-8500a on the pharmacokinetics of statins, we evaluated the effects of repeated oral administration of DS-8500a 75 mg on the pharmacokinetics of rosuvastatin and atorvastatin in healthy adults. METHODS We performed two single-center, open-label, single-sequence studies. In Study I, subjects received single-dose rosuvastatin 10 mg (Period A) and DS-8500a 75 mg once daily + single-dose rosuvastatin 10 mg (Period B). In Study II, subjects received single-dose atorvastatin 10 mg (Period A) and DS-8500a 75 mg once daily + single-dose atorvastatin 10 mg (Period B). Primary pharmacokinetic endpoints were maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of rosuvastatin and atorvastatin. Safety was evaluated. RESULTS In Study I, the Cmax and AUC of rosuvastatin increased by 66% and 33%, respectively, when coadministered with DS-8500a, versus rosuvastatin alone. In Study II, the Cmax of atorvastatin increased by 28%, but AUC remained unchanged following coadministration with DS-8500a, versus atorvastatin alone. Treatment-emergent adverse events were mild to moderate and mostly unrelated to the study drugs. CONCLUSIONS Multiple doses of DS-8500a increased exposure to rosuvastatin and atorvastatin. This short-term study suggests that the impact of DS-8500a coadministration on atorvastatin exposure is limited and may not be clinically relevant. Nevertheless, caution may be necessary when patients are coadministered rosuvastatin with DS-8500a. CLINICALTRIALS. GOV IDENTIFIER NCT03699774. JAPAN PHARMACEUTICAL INFORMATION CENTER IDENTIFIER JapicCTI-152878.
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7.
Discovery of Human Signaling Systems: Pairing Peptides to G Protein-Coupled Receptors.
Foster, SR, Hauser, AS, Vedel, L, Strachan, RT, Huang, XP, Gavin, AC, Shah, SD, Nayak, AP, Haugaard-Kedström, LM, Penn, RB, et al
Cell. 2019;(4):895-908.e21
Abstract
The peptidergic system is the most abundant network of ligand-receptor-mediated signaling in humans. However, the physiological roles remain elusive for numerous peptides and more than 100 G protein-coupled receptors (GPCRs). Here we report the pairing of cognate peptides and receptors. Integrating comparative genomics across 313 species and bioinformatics on all protein sequences and structures of human class A GPCRs, we identify universal characteristics that uncover additional potential peptidergic signaling systems. Using three orthogonal biochemical assays, we pair 17 proposed endogenous ligands with five orphan GPCRs that are associated with diseases, including genetic, neoplastic, nervous and reproductive system disorders. We also identify additional peptides for nine receptors with recognized ligands and pathophysiological roles. This integrated computational and multifaceted experimental approach expands the peptide-GPCR network and opens the way for studies to elucidate the roles of these signaling systems in human physiology and disease. VIDEO ABSTRACT.
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8.
Activation of HCAR2 by niacin: benefits beyond lipid lowering.
Tuteja, S
Pharmacogenomics. 2019;(16):1143-1150
Abstract
Niacin (nicotinic acid) is a potent lipid-lowering agent that has been used for prevention of coronary heart disease. Niacin activates the HCAR2 receptor found on adipocytes, macrophages and various immune cells throughout the body. Activation of the HCAR2 receptor by niacin results in beneficial anti-inflammatory effects that are independent of lipid lowering. This review summarizes the use of niacin in treatment of dyslipidemia, the pharmacogenetics of niacin response and the potential role of HCAR2 signaling in the treatment of a variety of inflammatory and metabolic diseases.
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9.
TAS2R38 Bitterness Receptor Genetic Variation and Risk of Gastrointestinal Neoplasm: A Meta-Analysis.
Choi, JH, Kim, J
Nutrition and cancer. 2019;(4):585-593
Abstract
Genetic variation in TAS2R38 bitterness taste receptor could alter the efficacy of molecular sensing, hence may be associated with cancer risk. Thus, we performed a meta-analysis to verify the association between the risk of gastrointestinal (GI) neoplasm and TAS2R38 genetic variation. Studies with TAS2R38 diplotype distribution and GI neoplasm phenotypes were searched from PubMed, EMBASE and SCOPUS, and five articles including eight studies were finally selected. The association between diplotype and neoplasm risk was estimated with summarized odds ratios (ORs) and 95% confidence intervals (CIs), applying of fixed- or random-effects models. The findings suggested TAS2R38 diplotype was not associated with GI neoplasms susceptibility [AVI vs. PAV: OR = 1.03 (95%CI: 0.97-1.09), AVI/PAV vs. PAV/PAV: OR = 1.05, (95%CI: 0.94-1.17), AVI/* vs. PAV/PAV: OR = 1.04 (95%CI: 0.94-1.16)]. Because of the presence of heterogeneity under the two genetic models (AVI/AVI vs. PAV/PAV and AVI/AVI vs. PAV/*), further subgroup analyses by ethnicity and neoplasm type were performed. However, results failed to show the neoplasm risk was altered by diplotype. In conclusion, the meta-analysis indicates that TAS2R38 diplotype minimally modified the GI neoplasm risk. Given the limited study size and resources, further well-designed and larger studies are required to validate the true effect of TAS2R38 polymorphisms on neoplasm risk.
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10.
GPER Mediates a Feedforward FGF2/FGFR1 Paracrine Activation Coupling CAFs to Cancer Cells toward Breast Tumor Progression.
Santolla, MF, Vivacqua, A, Lappano, R, Rigiracciolo, DC, Cirillo, F, Galli, GR, Talia, M, Brunetti, G, Miglietta, AM, Belfiore, A, et al
Cells. 2019;(3)
Abstract
The FGF2/FGFR1 paracrine loop is involved in the cross-talk between breast cancer cells and components of the tumor stroma as cancer-associated fibroblasts (CAFs). By quantitative PCR (qPCR), western blot, immunofluorescence analysis, ELISA and ChIP assays, we demonstrated that 17β-estradiol (E2) and the G protein estrogen receptor (GPER) agonist G-1 induce the up-regulation and secretion of FGF2 via GPER together with the EGFR/ERK/c-fos/AP-1 signaling cascade in (ER)-negative primary CAFs. Evaluating the genetic alterations from METABRIC and TCGA datasets, we then assessed that FGFR1 is the most frequently amplified FGFRs family member and its amplification/expression associates with shorter survival rates in breast cancer patients. Therefore, in order to assess the functional FGF2/FGFR1 interplay between CAFs and breast cancer cells, we generated the FGFR1-knockout MDA-MB-231 cells using CRISPR/Cas9 genome editing strategy. Using conditioned medium from estrogen-stimulated CAFs, we established that the activation of FGF2/FGFR1 paracrine signaling triggers the expression of the connective tissue growth factor (CTGF), leading to the migration and invasion of MDA-MB-231 cells. Our findings shed new light on the role elicited by estrogens through GPER in the activation of the FGF2/FGFR1 signaling. Moreover, our findings may identify further biological targets that could be considered in innovative combination strategies halting breast cancer progression.