The concept that G protein‐coupled receptors (GPCRs) can form hetero‐dimers or hetero‐oligomers continues to gain experimental support. However, with the exception of the GABAB receptor and the sweet ...and umami taste receptors few reported examples meet all of the criteria suggested in a recent International Union of Basic and Clinical Pharmacology sponsored review (Pin et al., 2007) that should be required to define distinct and physiologically relevant receptor species. Despite this, there are many examples in which pairs of co‐expressed GPCRs reciprocally modulate their function, trafficking and/or ligand pharmacology. Such data are at least consistent with physical interactions between the receptor pairs. In recent times, it has been suggested that specific GPCR hetero‐dimer or hetero‐oligomer pairs may represent key molecular targets of certain clinically effective, small molecule drugs and there is growing interest in efforts to identify ligands that may modulate hetero‐dimer function selectively. The current review summarizes key recent developments in these topics.
The concept that G-protein-coupled receptors can exist as homomeric and/or heteromeric complexes is now well established. Despite this, how dynamic such interactions are and if this may be modulated ...during receptor trafficking remain topics of debate. Use of endoplasmic reticulum trapping strategies and the generation of asymmetric homomers have started to provide information on the contribution of protein–protein interactions to receptor maturation, cell surface delivery and ligand-mediated endocytosis. Although dimer/oligomer formation appears to be essential for cell surface delivery of class A and class C GPCRs, this may not be the case for class B receptors.
GPR35 is a poorly characterized G protein-coupled receptor (GPCR) that has been suggested as a potential therapeutic target for the treatment of diabetes, hypertension and asthma. Two endogenously ...produced ligands have been suggested as activators of GPR35, although the relevance of these remains unclear. Recently, a series of surrogate agonist ligands and the first antagonists of GPR35 have been identified. However, marked differences in the potency of agonists at species orthologues of GPR35 have been noted, and this presents substantial challenges in translating the pharmacology at the cloned human receptor to ex vivo and in vivo studies of the physiological function of this receptor in animal models. Currently identified agonists will probably not display high selectivity for GPR35. By contrast, comparisons of the potency of ligands at species orthologues of GPR35 have provided insight into the nature of the ligand binding pocket and could result in the identification of more potent and selective ligands.
It is now generally accepted that G protein-coupled receptors (GPCRs) can exist as dimers or as part of larger oligomeric complexes. Increasing evidence suggests that a dimer is the minimal ...functional structure, but considerable variation exists between reports of the effects of agonist ligands on quaternary structure. Many studies have intimated the existence of heterodimeric GPCR pairings. Key questions that remain to be addressed effectively include the prevalence and relevance of these in native tissues and the implications of heterodimerization for pharmacology and, potentially, for drug design.
G protein-coupled receptors (GPCRs) are historically the most successful family of drug targets. In recent times it has become clear that the pharmacology of these receptors is far more complex than ...previously imagined. Understanding of the pharmacological regulation of GPCRs now extends beyond simple competitive agonism or antagonism by ligands interacting with the orthosteric binding site of the receptor to incorporate concepts of allosteric agonism, allosteric modulation, signaling bias, constitutive activity, and inverse agonism. Herein, we consider how evolving concepts of GPCR pharmacology have shaped understanding of the complex pharmacology of receptors that recognize and are activated by nonesterified or “free” fatty acids (FFAs). The FFA family of receptors is a recently deorphanized set of GPCRs, the members of which are now receiving substantial interest as novel targets for the treatment of metabolic and inflammatory diseases. Further understanding of the complex pharmacology of these receptors will be critical to unlocking their ultimate therapeutic potential.
Despite some blockbuster G protein-coupled receptor (GPCR) drugs, only a small fraction (∼ 15%) of the more than 390 nonodorant GPCRs have been successfully targeted by the pharmaceutical industry. ...One way that this issue might be addressed is via translation of recent deorphanization programs that have opened the prospect of extending the reach of new medicine design to novel receptor types with potential therapeutic value. Prominent among these receptors are those that respond to short-chain free fatty acids of carbon chain length 2-6. These receptors, FFA2 (GPR43) and FFA3 (GPR41), are each predominantly activated by the short-chain fatty acids acetate, propionate, and butyrate, ligands that originate largely as fermentation by-products of anaerobic bacteria in the gut. However, the presence of FFA2 and FFA3 on pancreatic β-cells, FFA3 on neurons, and FFA2 on leukocytes and adipocytes means that the biologic role of these receptors likely extends beyond the widely accepted role of regulating peptide hormone release from enteroendocrine cells in the gut. Here, we review the physiologic roles of FFA2 and FFA3, the recent development and use of receptor-selective pharmacological tool compounds and genetic models available to study these receptors, and present evidence of the potential therapeutic value of targeting this emerging receptor pair.
For many years seven transmembrane domain G protein-coupled receptors (GPCRs) were thought to exist and function exclusively as monomeric units. However, evidence both from native cells and ...heterologous expression systems has demonstrated that GPCRs can both traffic and signal within higher-order complexes. As for other protein-protein interactions, conformational changes in one polypeptide, including those resulting from binding of pharmacological ligands, have the capacity to alter the conformation and therefore the response of the interacting protein(s), a process known as allosterism. For GPCRs, allosterism across homo- or heteromers, whether dimers or higher-order oligomers, represents an additional topographical landscape that must now be considered pharmacologically. Such effects may offer the opportunity for novel therapeutic approaches. Allosterism at GPCR heteromers is particularly exciting in that it offers additional scope to provide receptor subtype selectivity and tissue specificity as well as fine-tuning of receptor signal strength. Herein, we introduce the concept of allosterism at both GPCR homomers and heteromers and discuss the various questions that must be addressed before significant advances can be made in drug discovery at these GPCR complexes.
Over the last decade, the ability to detect agonist-independent signal transduction by G protein-coupled receptors has in turn resulted in the detection and study of ligands able to block this ...activity. Such ligands are generically described as inverse agonists. Considerable attention has recently been devoted to the presence and roles of endogenous antagonist/inverse agonists and the concept that inverse agonists may have specific therapeutic benefits compared with neutral antagonists.
•ABAQUS can be used to study the impact of column rectangularity on punching shear.•Slab shear stresses concentrate near the corner and along short side of the column.•Impact of column rectangularity ...on punching not a function of column geometry only.•Impact also dependent on ratio of minimum column dimension to effective slab depth.•ABAQUS results indicate that current American design methods may be unconservative.
Design provisions for punching shear of reinforced concrete flat slabs supported on rectangular columns vary greatly and are typically based on empirical results. Due to the large cost and time required to conduct experimental tests the empirical database for slabs supported on rectangular columns is small. Properly calibrated, nonlinear finite element models (FEM) provide an efficient way to expand experimental databases, conduct parametric studies and verify design provisions. In this paper, the results from a parametric study of the impact of column rectangularity (aspect ratio) on the punching shear behaviour of interior slab-column connections without shear reinforcement under static concentric vertical loading are provided. The study was conducted using a three-dimensional nonlinear FEM based on the concrete damaged plasticity model available in ABAQUS. The FEM, summarized herein, was calibrated using seven experimental specimens of slabs supported on square and rectangular columns from literature. The parameters studied were the column aspect ratio, and the ratio of the minimum column dimension to the effective slab depth. These parameters were selected based on a review of literature and design provisions. The impact of column rectangularity on the predicted load-deflection response, slab crack patterns and shear stress distribution in the slab along the column perimeter are analyzed. The results for the 77 slab-column connections simulated in the parametric study demonstrate that the impact of column rectangularity is not dependent on the column aspect ratio alone, and becomes more severe as the ratio of the minimum column dimension to the effective slab depth increases.
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