THE CONCISE GUIDE TO PHARMACOLOGY 2019/20: Introduction and Other Protein Targets

Background and Purpose G proteins are intracellular switches that transduce and amplify extracellular signals from GPCRs. The Gq protein subtypes, which are coupled to PLC activation, can act as oncogenes, and their expression was reported to be up‐regulated in cancer and inflammatory diseases. Gq inhibition may be an efficient therapeutic strategy constituting a new level of intervention. However, diagnostic tools and therapeutic drugs for Gq proteins are lacking. Experimental Approach We have now developed Gq‐specific, cell‐permeable 3H‐labelled high‐affinity probes based on the macrocyclic depsipeptides FR900359 (FR) and YM‐254890 (YM). The tracers served to specifically label and quantify Gq proteins in their native conformation in cells and tissues with high accuracy. Key Results FR and YM displayed low nanomolar affinity for Gαq, Gα11 and Gα14 expressed in CRISPR/Cas9 Gαq‐knockout cells, but not for Gα15. The two structurally very similar tracers showed strikingly different dissociation kinetics, which is predicted to result in divergent biological effects. Computational studies suggested a “dowel” effect of the pseudoirreversibly binding FR. A high‐throughput binding assay led to the discovery of novel Gq inhibitors, which inhibited Gq signalling in recombinant cells and primary murine brown adipocytes, resulting in enhanced differentiation. Conclusions and Implications The Gq protein inhibitors YM and FR are pharmacologically different despite similar structures. The new versatile tools and powerful assays will contribute to the advancement of the rising field of G protein research.

Section: Nomenclature Of Targets and Ligandsmentioning

confidence: 99%

Cell‐permeable high‐affinity tracers for G_q proteins provide structural insights, reveal distinct binding kinetics and identify small molecule inhibitors

Kuschak

Namasivayam

Rafehi

et al. 2020

“…Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Harding et al, ), and are permanently archived in the Concise Guide to PHARMACOLOGY 2019/20 (Alexander, Fabbro et al, ; Alexander, Kelly et al, ).…”

Section: Methodsmentioning

confidence: 99%

Treatment with anti‐neonatal Fc receptor (FcRn) antibody ameliorates experimental epidermolysis bullosa acquisita in mice

Kasprick

Hofrichter

Smith

et al. 2020

Background and Purpose: Pemphigus and pemphigoid diseases are characterized and caused predominantly by IgG autoantibodies targeting structural proteins of the skin. Their current treatment relies on general and prolonged immunosuppression that causes severe adverse events, including death. Hence, novel safe and more effective treatments are urgently needed. Due to its' physiological functions, the neonatal Fc receptor (FcRn) has emerged as a potential therapeutic target for pemphigus and pemphigoid, primarily because IgG is protected from proteolysis after uptake into endothelial cells. Thus, blockade of FcRn would reduce circulating autoantibody concentrations. However, long-term effects of pharmacological FcRn inhibition in therapeutic settings of autoimmune diseases are unknown. Experimental Approach: Therapeutic effects of FcRn blockade were investigated in a murine model of the prototypical autoantibody-mediated pemphigoid disease, epidermolysis bullosa acquisita (EBA). B6.SJL-H2s C3c/1CyJ mice with clinically active disease were randomized to receive either an anti-FcRn monoclonal antibody (4470) or an isotype control over 4 weeks. Key Results: While clinical disease continued to worsen in isotype control-treated mice, overall disease severity continuously decreased in mice injected with 4470, leading to almost complete remission in over 25% of treated mice. These clinical findings were paralleled by a reduction of autoantibody concentrations. Reduction of autoantibody concentrations, rather than modulating neutrophil activation, was responsible for the observed therapeutic effects. Conclusion and Implications: The clinical efficacy of anti-FcRn treatment in this prototypical autoantibody-mediated disease encourages further development of anti-FcRn antibodies for clinical use in pemphigoid diseases and potentially in other autoantibody mediated diseases.Abbreviations: AIBD, autoimmune bullous dermatoses; COL7, type VII collagen; EBA, epidermolysis bullosa acquisita; FcRn, neonatal Fc receptor; PD, pemphigoid diseases. Ralf J. Ludwig and Enno Schmidt contributed equally to this study.

“…Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMA-COLOGY (Harding et al, 2018) and are permanently archived in the Concise Guide to PHARMACOLOGY 2019/2020 (Alexander et al, 2019).…”

Section: Nomenclature Of Targets and Ligandsmentioning

confidence: 99%

Ca²⁺ signalling in fibroblasts and the therapeutic potential of K_Ca3.1 channel blockers in fibrotic diseases

Roach

Bradding

2020

The role of Ca2+ signalling in fibroblasts is of great interest in fibrosis‐related diseases. Intracellular free Ca2+ ([Ca2+]i) is a ubiquitous secondary messenger, regulating a number of cellular functions such as secretion, metabolism, differentiation, proliferation and contraction. The intermediate conductance Ca2+‐activated K+ channel KCa3.1 is pivotal in Ca2+ signalling and plays a central role in fibroblast processes including cell activation, migration and proliferation through the regulation of cell membrane potential. Evidence from a number of approaches demonstrates that KCa3.1 plays an important role in the development of many fibrotic diseases, including idiopathic pulmonary, renal tubulointerstitial fibrosis and cardiovascular disease. The KCa3.1 selective blocker senicapoc was well tolerated in clinical trials for sickle cell disease, raising the possibility of rapid translation to the clinic for people suffering from pathological fibrosis. This review after analysing all the data, concludes that targeting KCa3.1 should be a high priority for human fibrotic disease.