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The past decade has witnessed a dramatic increase in the identification of allosteric modulators of G-protein-coupled receptor (GPCR) activity. Concomitantly, several new perspectives and hypotheses regarding the way ligands regulate GPCR signalling have also emerged. Here, we briefly discuss how the concepts of collateral efficacy and permissive(More)
BACKGROUND AND PURPOSE We recently characterized LY2033298 as a novel allosteric modulator and agonist at M(4) muscarinic acetylcholine receptors (mAChRs). Evidence also suggested a difference in the potency of LY2033298 at rodent relative to human M(4) mAChRs. The current study investigated the basis for the species difference of this modulator and used(More)
Diet and the gut microbiota may underpin numerous human diseases. A major metabolic product of commensal bacteria are short-chain fatty acids (SCFAs) that derive from fermentation of dietary fibre. Here we show that diets deficient or low in fibre exacerbate colitis development, while very high intake of dietary fibre or the SCFA acetate protects against(More)
Phenotyping of Gprc6a KO mice has shown that this promiscuous class C G protein coupled receptor is variously involved in regulation of metabolism, inflammation and endocrine function. Such effects are described as mediated by extracellular calcium, L-amino acids, the bone-derived peptide osteocalcin (OCN) and the male hormone testosterone, introducing the(More)
We recently identified LY2033298 as a novel allosteric potentiator of acetylcholine (ACh) at the M(4) muscarinic acetylcholine receptor (mAChR). This study characterized the molecular mode of action of this modulator in both recombinant and native systems. Radioligand-binding studies revealed that LY2033298 displayed a preference for the active state of the(More)
The calcium-sensing receptor (CaSR) is a G protein-coupled receptor whose function can be allosterically modulated in a positive or negative manner by calcimimetics or calcilytics, respectively. Indeed, the second-generation calcimimetic, cinacalcet, has proven clinically useful in the treatment of chronic kidney disease patients with secondary(More)
Calcium-sensing receptors (CaSRs) are class C G protein-coupled receptors that respond to physiological activators, including extracellular Ca2+ (Cao2+) and L-amino acids as well as the pharmaceutical calcimimetic, cinacalcet. Unlike Cao2+, which is an orthosteric agonist, L-amino acids and cinacalcet are positive allosteric modulators. CaSR expression(More)
In addition to its acute effects on hormone secretion, epithelial transport, and shape change, the calcium-sensing receptor (CaSR) modulates the expression of genes that control cell survival, proliferation, and differentiation as well as the synthesis of peptide hormones and enzymes. In the present study, we investigated the impacts of a CaSR agonist and(More)
Cinacalcet is predominantly used to treat secondary hyperparathyroidism due to end-stage renal failure, but, more recently, its potential clinical efficacy in treating patients with loss-of-function mutations in the calcium-sensing receptor (CaSR) has been recognized. Many clinically relevant CaSR mutations are located in the heptahelical membrane spanning(More)
OBJECTIVES Describe current and future approaches to tissue engineering, specifically in the area of bone regeneration. These approaches will allow one to actively regulate the cellular populations participating in this process. DESIGN Many approaches to actively regulate cellular phenotype are under exploration, and these typically exploit known signal(More)