Community guidelines for GPCR ligand bias: IUPHAR review 32

GPCRs modulate a plethora of physiological processes and mediate the effects of one-third of FDA-approved drugs. Depending on which ligand activates a receptor, it can engage different intracellular transducers. This ‘biased signalling’ paradigm requires that we now characterize physiological signalling not just by receptors but by ligand–receptor pairs. Ligands eliciting biased signalling may constitute better drugs with higher efficacy and fewer adverse effects. However, ligand bias is very complex, making reproducibility and description challenging. Here, we provide guidelines and terminology for any scientists to design and report ligand bias experiments. The guidelines will aid consistency and clarity, as the basic receptor research and drug discovery communities continue to advance our understanding and exploitation of ligand bias. Scientific insight, biosensors, and analytical methods are still evolving and should benefit from and contribute to the implementation of the guidelines, together improving translation from in vitro to disease-relevant in vivo models

A role for the sodium pump in H2O2-induced vasorelaxation in porcine isolated coronary arteries

Hydrogen peroxide (H2O2) has been proposed to act as a factor for endothelium-derived hyperpolar-ization (EDH) and EDH may act as a ‘back up’ system to compensate the loss of the NO pathway. Here,the mechanism of action of H2O2in porcine isolated coronary arteries (PCAs) was investigated. DistalPCAs were mounted in a wire myograph and pre-contracted with U46619 (1 nM–50 muM), a throm-boxane A2-mimetic or KCl (60 mM). Concentration–response curves to H2O2(1 muM–1 mM), bradykinin(0.01 nM–1 muM), sodium nitroprusside (SNP) (10 nM–10 muM), verapamil (1 nM–10 muM), KCl (0–20 mM)or Ca2+-reintroduction (1 muM–10 mM) were constructed in the presence of various inhibitors. Activityof the Na+/K+-pump was measured through rubidium-uptake using atomic absorption spectropho-tometry. H2O2caused concentration-dependent vasorelaxations with a maximum relaxation (Rmax) of100 ± 16% (mean ± SEM), pEC50= 4.18 ± 0.20 (n = 4) which were significantly inhibited by PEG-catalase at0.1–1.0 mM H2O2(P < 0.05). 10 mM TEA significantly inhibited the relaxation up to 100 muM H2O2(P < 0.05).60 mM K+and 500 nM ouabain significantly inhibited H2O2-induced vasorelaxation producing a relax-ation of 40.8 ± 8.5% (n = 5) and 47.5 ± 8.6% (n = 6) respectively at 1 mM H2O2(P < 0.0001). H2O2-inducedvasorelaxation was unaffected by the removal of endothelium, inhibition of NO, cyclo-oxygenase, gapjunctions, SKCa, IKCa, BKCaKir, KV, KATPor cGMP. 100 muM H2O2had no effects on the KCl-induced vasore-laxation or Ca2+-reintroduction contraction. 1 mM H2O2inhibited both KCl-induced vasorelaxation andrubidium-uptake consistent with inhibition of the Na+/K+-pump activity. We have shown that the vas-cular actions of H2O2are sensitive to ouabain and high concentrations of H2O2are able to modulate theNa+/K+-pump. This may contribute towards its vascular actions

The concise guide to PHARMACOLOGY 2013/14: overview

The Concise Guide to PHARMACOLOGY 2013/14 provides concise overviews of the key properties of over 2000 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands, which provides more detailed views of target and ligand properties from the IUPHAR database. This compilation of the major pharmacological targets is divided into seven areas of focus: G protein-coupled receptors, ligand-gated ion channels, ion channels, catalytic receptors, nuclear hormone receptors, transporters and enzymes. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. A new landscape format has easy to use tables comparing related targets.&lt;p&gt;&lt;/p&gt; It is a condensed version of material contemporary to late 2013, which is presented in greater detail and constantly updated on the website, superseding data presented in previous Guides to Receptors &#38; Channels. It is produced in conjunction with NC-IUPHAR and provides the official IUPHAR classification and nomenclature for human drug targets, where appropriate. It consolidates information previously curated and displayed separately in IUPHAR-DB and GRAC and provides a permanent, citable, point-in-time record that will survive database updates.&lt;p&gt;&lt;/p&gt