The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein‐coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

We investigated the direct effects of changes in free ionized extracellular calcium concentrations ([Ca 2؉ ]o) on osteoblast function and the involvement of the calcium-sensing receptor (CaR) in mediating these responses. CaR mRNA and protein were detected in osteoblast models, freshly isolated fetal rat calvarial cells and murine clonal osteoblastic 2T3 cells, and in freshly frozen, undecalcified preparations of human mandible and rat femur. In fetal rat calvarial cells, elevating [Ca 2؉ ]o and treatment with gadolinium, a nonpermeant CaR agonist, resulted in phosphorylation of the extracellular signal-regulated kinases 1 and 2, Akt, and glycogensynthase kinase 3␤, consistent with signals of cell survival and proliferation. In agreement, cell number was increased under these conditions. Expression of the osteoblast differentiation markers core binding factor ␣1, osteocalcin, osteopontin, and collagen I mRNAs was increased by high [ (2, 3) and alter the levels of expression of some differentiation markers (4, 5). During mineralization, decreases in [Ca 2ϩ ] o are also likely to occur (6), but the effect of lowering [Ca 2ϩ ] o in bone cells has not been extensively addressed.The mechanism of [Ca 2ϩ ] o -sensing by osteoblasts is unclear. The parathyroid extracellular calcium-sensing receptor (CaR) is a key player in the maintenance of a constant systemic [Ca 2ϩ ] o , predominantly through regulation of parathyroid hormone (PTH) secretion and urinary calcium excretion (7,8). CaR is also present in osteoblasts (9 and references therein), where a functional role is currently debated. Recently two studies have shown that CaRdeficient mice exhibit an essentially normal skeletal phenotype when the hyperparathyroidism resulting from the lack of the parathyroid CaR is prevented (10, 11). Thus, it remains unclear whether the osteoblast CaR is a true regulator of bone function or whether its expression is vestigial (12).In this study, we investigated the effects of both decreasing and increasing [Ca 2ϩ ] o on osteoblast proliferation and intracellular signaling events, the expression of several osteoblast differentiation markers [core binding factor ␣1 (Cbfa1, also termed Runx2 and Osf2), osteocalcin (OC), osteopontin (OP), and type I collagen (collaI)], the activity of alkaline phosphatase (AlP), and mineralized nodule formation in the absence of systemic calciotropic factors, namely PTH and vitamin D. We further investigated the role played by the CaR in these events using an alternative, nonpermeant CaR agonist, gadolinium (Gd 3ϩ ) and a CaR inhibitor, NPS 89636 (a ''calcilytic''). We used well characterized osteoblast models, freshly isolated fetal rat calvarial cells (FRC) (13) and the clonal murine osteoblast cell line, 2T3 cells (14). The expression of CaR in freshly frozen sections of rat and human bone was also determined. Materials and MethodsAnimals. Sprague-Dawley rats (Charles River Breeding Laboratories) were killed by cervical dislocation and used in accordance to the U.K. Animals Scientific Procedures...

Airway hyperresponsiveness and inflammation are fundamental hallmarks of allergic asthma that are accompanied by increases in certain polycations, such as eosinophil cationic protein. Levels of these cations in body fluids correlate with asthma severity. We show that polycations and elevated extracellular calcium activate the human recombinant and native calcium-sensing receptor (CaSR), leading to intracellular calcium mobilization, cyclic adenosine monophosphate breakdown, and p38 mitogen-activated protein kinase phosphorylation in airway smooth muscle (ASM) cells. These effects can be prevented by CaSR antagonists, termed calcilytics. Moreover, asthmatic patients and allergen-sensitized mice expressed more CaSR in ASMs than did their healthy counterparts. Indeed, polycations induced hyper-reactivity in mouse bronchi, and this effect was prevented by calcilytics and absent in mice with CaSR ablation from ASM. Calcilytics also reduced airway hyperresponsiveness and inflammation in allergen-sensitized mice in vivo. These data show that a functional CaSR is up-regulated in asthmatic ASM and targeted by locally produced polycations to induce hyperresponsiveness and inflammation. Thus, calcilytics may represent effective asthma therapeutics.

Abstract-Small increases in extracellular Ca2ϩ dilate isolated blood vessels. In the present study, the possibility that a vascular, extracellular Ca 2ϩ -sensing receptor (CaSR) could mediate these vasodilator actions was investigated. Novel ligands that interact with the CaSR were used in microelectrode recordings from rat isolated mesenteric and porcine coronary arteries. The major findings were that (1)