Modulation of Glucagon Receptor Pharmacology by Receptor Activity-modifying Protein-2 (RAMP2).

The glucagon and glucagon-like peptide-1 (GLP-1) receptors play important, opposing roles in regulating blood glucose levels. Consequently, these receptors have been identified as targets for novel diabetes treatments. However, drugs acting at the GLP-1 receptor, although having clinical efficacy, have been associated with severe adverse side-effects, and targeting of the glucagon receptor has yet to be successful. Here we use a combination of yeast reporter assays and mammalian systems to provide a more complete understanding of glucagon receptor signaling, considering the effect of multiple ligands, association with the receptor-interacting protein receptor activity-modifying protein-2 (RAMP2), and the role of individual G protein α-subunits. We demonstrate that RAMP2 alters both ligand selectivity and G protein preference of the glucagon receptor. Importantly, we also uncover novel cross-reactivity of therapeutically used GLP-1 receptor ligands at the glucagon receptor that is abolished by RAMP2 interaction. This study reveals the glucagon receptor as a previously unidentified target for GLP-1 receptor agonists and highlights a role for RAMP2 in regulating its pharmacology. Such previously unrecognized functions of RAMPs highlight the need to consider all receptor-interacting proteins in future drug development.This work was supported by a Warwick Impact Fund (C.W., G.L.), the BBSRC (G.L. - BB/G01227X/1), (T.S., G.R., D.R. - BB/F008392/1), (D.P. - BB/M007529/1 and BB/M000176/1), Warwick Research Development Fund (C.W., G.L.) grant number (RD13301) and the Birmingham Science City Research Alliance (G.L).This is the final version of the article. It first appeared from ASBMB at http://dx.doi.org/10.1074/jbc.M114.62460

A modified three terms PRP conjugate gradient method

In order to effectively solve a class of large-scale unconstrained optimization problems and overcome the shortcomings of other algorithms, such as complex algorithms, large memory and computer programming difficulties, a new search direction is defined, which is based on some traditional three terms PRP conjugate gradient methods as well as combined with the research results of three terms conjugate gradient and some new line searches in recent years. A new line search algorithm is used to construct the algorithm, which proves that it has the properties of automatic full descent and trust region, and proves its global convergence under appropriate conditions. Numerical experiments has showed that the new algorithm is more competitive than the traditional three-term PRP conjugate gradient method in solving a class of large-scale unconstrained optimization problems. The new algorithm with better convergence property provides a more efficient algorithm basis for solving a class of large-scale unconstrained optimization problems

Design and analysis of lumped resistor loaded metamaterial absorber with transmission band

A new type of multi-layer metamaterial (MM) absorber is represented in this paper, which behave as a dielectric slab in transmission band and act as an absorber in another lower band. The equivalent circuit model of each layer in this MM absorber has been established. The transmission line (TL) model is introduced to analysis the mechanism of electromagnetic wave traveling through this MM absorber. Both theoretical and experimental results indicate this MM absorber has a transmission band at 21GHz and an absorptive band from 5GHz to 13GHz. A good match of TL model results and measurement results verified the validity of TL model in analyzing and optimizing the performances of this kind of absorber

Enhancing the Terahertz Absorption Spectrum Based on the Low Refractive Index All-Dielectric Metasurface

We presented an angle-multiplexing low refractive index dielectric metasurface for terahertz absorption spectrum enhancement of lactose with high Q resonance properties. The unit cell structure of the acrylonitrile butadiene styrene (ABS) square structure is designed and optimized. The resonant peak shifts of the dielectric metasurface are analyzed by changing the incident angle of the terahertz wave. Then the α-lactose films with different thicknesses are added to investigate the enhancement effect. The resonant peak amplitude of the angle-multiplexing low refractive index dielectric metasurface absorption spectrum changes greatly with the absorption spectrum of the samples. The results illustrate that the enhanced absorption spectrum formed by the linked envelope can be up to 45 times stronger than that without the unit cell structures and also exhibits a high-quality factor. The proposed dielectric metasurface provides great potential in enhancing the terahertz absorption spectrum

The Bragg gap vanishing phenomena in one-dimensional photonic crystals

We theoretically deduce the Bragg gap vanishing conditions in one-dimensional photonic crystals and experimentally demonstrate the m=0 band-gap vanishing phenomena at microwave frequencies. In the case of mismatched impedance, the Bragg gap will vanish as long as the discrete modes appear in photonic crystals containing dispersive materials, while for the matched impedance cases, Bragg gaps will always disappear. The experimental results and the simulations agree extremely well with the theoretical expectation

Enhancing the Terahertz Absorption Spectrum Based on the Low Refractive Index All-Dielectric Metasurface

We presented an angle-multiplexing low refractive index dielectric metasurface for terahertz absorption spectrum enhancement of lactose with high Q resonance properties. The unit cell structure of the acrylonitrile butadiene styrene (ABS) square structure is designed and optimized. The resonant peak shifts of the dielectric metasurface are analyzed by changing the incident angle of the terahertz wave. Then the α-lactose films with different thicknesses are added to investigate the enhancement effect. The resonant peak amplitude of the angle-multiplexing low refractive index dielectric metasurface absorption spectrum changes greatly with the absorption spectrum of the samples. The results illustrate that the enhanced absorption spectrum formed by the linked envelope can be up to 45 times stronger than that without the unit cell structures and also exhibits a high-quality factor. The proposed dielectric metasurface provides great potential in enhancing the terahertz absorption spectrum

ERK signaling through the GLP-1R.

<p>HEK-GLP-1R cells (<b>A and B</b>) or INS-1E cells (<b>C and D</b>) were challenged for 5 min with either vehicle (1% v/v DMSO), GLP-1 9–36 amide (1 or 10 µM as indicated) or compound 2 alone or GLP-1 9–36 amide (1 µM) and compound 2 together as indicated. Cells were also challenged with GLP-1 7–36 amide (10 nM). Levels of phospho-ERK were then determined by Western blotting. The intensity of the bands representing phospho-ERK was determined using ImageJ and the mean data are shown in the panels below the immunoblot with basal (0) levels subtracted. Data are either representative of 3 experiments or mean+s.e.m., n = 3. *, P<0.05 and ** P<0.01 by Student's test versus the numerical sum of both GLP-1 9–36 amide (1 µM) and compound 2 at the concentration indicated when used alone.</p

Functional interaction between ligands on GLP-1R-mediated cAMP generation in HEK-GLP-1R cells.

<p>HEK-GLP-1R cells were pretreated (Pre-) for 10 min with 1 µM GLP-1 9–36 amide in the presence of IBMX before challenge for 15 min with the indicated concentrations of agonists. Where no pre-treatment is indicated, an equivalent volume of buffer (KHB) was added for 10 min in the presence of IBMX prior to ligand addition for 15 min. Levels of intracellular cAMP were then determined relative to the cellular protein content. The final concentration of DMSO (vehicle) for the 15 min treatment period was 5% v/v in all cases. Data are mean±s.e.m., n = 3.</p