The GtoPdb team need no convincing about the importance of eliminating equivocality in gene and gene product names, as they are used in the pharmacology, chemical biology and drug discovery literature. Crucially, this also applies to their inclusion in curated…
Historically, the main classes of drug targets have been receptors, enzymes, ion channels and transporters which are primarily targeted by small molecules. However, advances in molecular biology, genomics, and pharmacology have facilitated the development of different therapeutic modalities which in…
It is now clear that ligand-gated ion channels (LGICs) are not “stand alone” functional units, but form complexes with other components, including scaffolding proteins, regulatory proteins and enzymes. Besides their important physiological roles, these modulating proteins are also potential targets…
This post covers three recent publications with a common theme and whose authors are collaborators with GtoPdb, thus making them as a trio particularly suitable for combined review. These are; Discovery of Human Signaling Systems: Pairing Peptides to G Protein-Coupled…
Melatonin targets two high-affinity receptors, MT1 and MT2, that belong to the G protein-coupled receptor (GPCR) superfamily (1,2). Drugs acting on melatonin receptors are subscribed for circadian disorders (jet lag, shift work, etc.), insomnia and major depression (3). All marketed…
Thirty eight years after the discovery that injection of the catalytic subunits of cyclic AMP-dependent protein kinase A (PKA) into isolated pig ventricular cardiac myocytes (1) increases the amplitude of L-type Ca2+ current (today known to be formed by Cav1.2…
Two new reports cover further aspects of cannabinoid receptor binding as defined using cryo-EM. These expand on previous reports of the structure of the human CB1 cannabinoid receptor with the antagonists taranabant and AM6538 bound, and with the agonists MDMB-FUBINACA,…
The new respiratory coronavirus from Wuhan in China is causing intense research activity in the world. Viruses are evidently associated with respiratory infections ranging in severity from the common cold to pneumonia and death
Nieng Yan’s group has now published the cryo-EM structure of the selective T-type Ca2+ channel blocker Z944 bound to the pore-forming α1-subunit of Cav3.1 T-type Ca2+ channels (1). This nicely adds to recent publications reporting of the high-resolution structures of…
Leukotrienes are lipid mediators of inflammation, initially recognized for their role in asthma, but also having potent effects in for example cardiovascular and neurological diseases as well as in cancer. The initial pharmacological classification of leukotriene receptors based on antagonist…
Muscarinic receptors consist of 5 G protein-coupled receptors which along with nicotinic ion channels mediate the effects of acetylcholine. Despite years of research on the role of muscarinic receptors in the brain and periphery the Muscarinic M5 receptor has stood…
P2X receptors are ligand-gated cation channels for which ATP is the endogenous orthosteric agonist. Seven P2X subunits have been identified and they form trimers to produce at least twelve different receptor subtypes. The tertiary structure of several subtypes have been…
The cross-talk between different G protein-coupled receptor signal-transduction pathways is an intriguing concept with important physiological implications [1]. A recent study by Wang et al. [2] has discovered that the actions of opioid drugs on the μ-opioid receptor (MOR) are…
In this report the Catterall laboratory succeeded in solving the high resolution structure of a voltage-gated Na+-channel (Nav) in its resting state (1). Why is this difficult and why is this important? It is difficult because Navs exist in the…
G protein-coupled receptors (GPCRs) are an important family of signal-transducing membrane proteins capable of binding various types of ligands from the extracellular space and activating various signalling pathways inside the cell, rendering them one of the largest protein target families…
We have now made the third IUPHAR/BPS Guide to Pharmacology database release of 2019 (2019.3). It includes updates focussed on preparation for the next edition of The Concise Guide to PHARMACOLOGY (2019/20), due out later this year. Content Updates GtoPdb…
G protein coupled receptors (GPCRs) are crucial for the transduction of extracellular stimuli to the intracellular space. Upon activation, GPCRs undergo large conformational changes to engage transducers and stimulate intracellular responses. However, the kinetics of agonist induced GPCR conformational changes…
A recent commentary in Nature has the provocative title “Retire Statistical Significance” (1, with a list of more than 800 signatories) and has been widely interpreted as a call for the entire concept of statistical significance to be abandoned. Closer…
Whilst life is always exciting as an ion channel pharmacologist, the last few months have been particularly so, with a large number of publications showing structures of ion channels with regulatory molecules bound to them. In just the last month,…
New machine learning algorithm for drug discovery that is twice as efficient as the industry standard and identified potential ligands for the M1 receptor, a potential target for the treatment of Alzheimer’s disease. A paper from Lee et al. [1]…
G protein-coupled receptors (GPCRs) transduce physiological and sensory stimuli into appropriate cellular responses and mediate the actions of one-third of drugs. Structures of GPCRs are therefore extremely valuable for understanding basic receptor function and rational drug design. Today, 310 structures…
Cannabinoid receptors respond to multiple endogenous fatty acid derivatives and are often divided into neuronal-associated CB1 receptors and immune cell-associated CB2 receptors. Both receptors are GPCR, coupled predominantly to Gi, and have cytoprotective properties. The predominant psychotropic agent in Cannabis, THC,…
Comments by Dr. Nicola J. Smith, National Heart Foundation Future Leader Fellow & Group Leader, Molecular Pharmacology Laboratory, Victor Chang Cardiac Research Institute, Australia As is often the case with orphan GPCRs, assigning the endogenous ligand has been controversial for the…
A new facet of the human brain has been reported [1] involving a first example of somatic gene recombination in neurons, representing a normal neural mechanism whose disruption could underlie the most common (sporadic) forms of Alzheimer’s disease. Mosaic and…
The cellular thermal shift assay (CETSA) was introduced in July of 2013 as a means to investigate drug target engagement inside live cells and tissues (1). The underlying principle of CETSA is simple – it relies on the thermostability of…
Piezo channels (Piezo1 and Piezo2) are excitatory ion channels which respond directly to a variety of forms of mechanical stimuli. Two recent papers describe some of the critical roles of Piezo channels in sensory neuron transduction (1, 2). In the…
The receptor tyrosine phosphatase (RTP) family is a relatively small group of cell-surface proteins with a simple intracellular enzymatic function in the dephosphorylation of phosphotyrosine proteins. There is less known about the endogenous extracellular ligands which regulate RTP activities in…
The unfortunate French clinical trial disaster in which the FAAH inhibitor BIA 10-2747 (ligand ID 9001) left one participant dead and several others with serious neurological adverse events, occurred back in January 2016. However, the primary publication that describes the properties…
In this multi-author, multi-centre publication [1] lead by Denise Wootten and Patrick Sexton from the Monash Institute of Pharmacological Sciences, there is reported a 3.3 Angstrom structure of one of the more unusual G protein-coupled receptors. The CGRP receptor is…
This paper [1] extends previous studies demonstrating a key role of voltage-gated L-type Ca2+ channels in the modulation of activity-dependent gene transcription. Earlier work in cultured neurons had already shown that L-type channel activity is required to activate gene expression…
July 2018 News, Updates and Hot Topics Database release 2018.3: Our third database release of the year, 2018.3, is now available. This update contains the following new features and content changes: Updates across several target classes. The existing Antimalarial targets…
The potassium channels KV7.2-KV7.5 (KCNQ2-5; GtoPdb target IDs 561-564) regulate neuronal excitability in the mammalian nervous system. The best characterised neuronal KV7 channels give rise to the M current (1) and are mediated predominantly by hetero-tetramers of KV7.2 and KV7.3…
A new type of deorphanization conundrum confronted in pairing the GPCR, MAS1 with the hormonal peptide angiotensin 1–7 (Ang1-7) was emphasised in recent IUPHAR reviews (1, 2). More evidence for disconnection between Ang1-7 and MAS1 is presented in the recent…
Every few years in the field of receptor pharmacology, a technological advance occurs that drives the field forward in terms of insight and understanding. Over the past couple of years, the cryo-EM technique (the development of which won the 2017…
What will Systems Biology look like in the future? Up to now, it has focussed on the development of standards, software tools and databases that enabled us to study the dynamics of physiological function mechanistically. However as these tools and…
The A1 adenosine receptor is, for most people, a molecular target they can become conscious of when they block it, which happens frequently. Rapid consumption of higher doses of caffeine, in products like Italian espresso or Turkish coffee, provokes a…
The Cannabis plant is a natural product from which more than 100 apparently unique metabolites (cannabinoids) have been identified. Many of these have been found in human plasma following consumption of Cannabis preparations. The most well-recognised is tetrahydrocannabinol, THC, because…
19 June 2018 update. Announced only about a week after the events described below, yet a third clinical candidate, lanabecestat (AZD-3293, LY3314814) has also bitten the dust (4). The two PhIII trials were stopped because they were deemed unlikely to meet their…
The A2A adenosine receptor is densely expressed in dopamine-rich areas of the brain and in the vasculature. It is the target of an adjunct medication for Parkinson’s Disease, istradefylline in Japan, an A2A receptor antagonist. The A2A adenosine receptor is an example…
The TRPV2 ion channel is the less well-characterised relative of the TRPV1 or vanilloid receptor that is activated by capsaicin. TRPV2 channels have many similarities to the TRPV1 channels, in that they are homotetrameric and respond to some of the same…
Negative allosteric modulators (NAMs) are of great interest in drug development because they offer improved scope for the production of receptor antagonists with enhanced subtype-selectivity. Indeed, many NAMs are already on the market or undergoing clinical trials. NAMs act by…
ASICs are potential drug targets of interest. Their activation mechanism has however remained elusive. ASICs are neuronal, proton-gated, sodium-permeable channels that are expressed in the central and peripheral nervous system of vertebrates. They form a subfamily of the Epithelial Na…
In order to stabilize the GPCR-G protein complex, an agonist must be bound to the receptor and the alpha subunit of the heterotrimer must be in a nucleotide-free state. Ground-breaking work by expert crystallographers made use of so-called mini G…
Contemporary drug discovery is dominated by two related themes. The first of these is target validation upon which the sustainability of pharmaceutical R&D (in both the commercial and academic sectors) crucially depends. The second is the size of the pool of human…
Within the vast GPCR superfamily, orphans are described as receptors devoid of known endogenous ligands. They have been labeled as 7 transmembrane proteins by sequence homology and dispatched accordingly in the different GPCR subfamilies. They have attracted much attention given…
A system of rigorous clinical trials and regulation exist to ensure that a new drug is safe and effective when reaching the market. However, natural human genetic variation(s) may cause individuals to respond differently to the same medication. A collaboration…
New avenues for GPCR drug discovery have emerged owing to recent advances in receptor pharmacology, technological breakthroughs in structural biology and innovations in biotechnology. A collaboration between the Department of Drug Design and Pharmacology, University of Copenhagen (home of the…
The mucolipin subfamily of Transient Receptor Potential (TRP) channels, which consist of TRPML1, TRPML2, and TRPML3 (a.k.a. MCOLN1- 3), are Ca2+-permeable cation channels localized in intracellular endosomes and lysosomes. In response to cellular stimulation, TRPMLs mediate Ca2+ release from the…
As one of the first propositions for GPCRs being present in mitochondrial membranes, a recent report from Robert Friedlander and colleagues [1] follows on from previous work characterising synaptic and extrasynaptic mitochondria in human cortex (post-mortem samples) and their role…
Lysophospholipids (LPs) have myriad roles as extracellular signals that activate cognate G protein-coupled receptors (GPCRs) (2). LPs for which receptors have been reported include lysophosphatidic acid (LPA) (receptors: LPA1-6), sphingosine 1-phosphate (S1P1-5), lysophosphatidyl serine (LPS1-3, 2L (2L is a pseudogene…
