Literature DB >> 26650438

The Concise Guide to PHARMACOLOGY 2015/16: Overview.

Stephen Ph Alexander¹, Eamonn Kelly², Neil Marrion², John A Peters³, Helen E Benson⁴, Elena Faccenda⁴, Adam J Pawson⁴, Joanna L Sharman⁴, Christopher Southan⁴, O Peter Buneman⁵, William A Catterall⁶, John A Cidlowski⁷, Anthony P Davenport⁸, Doriano Fabbro⁹, Grace Fan¹⁰, John C McGrath¹¹, Michael Spedding¹², Jamie A Davies⁴.

Abstract

The Concise Guide to PHARMACOLOGY 2015/16 provides concise overviews of the key properties of over 1750 human drug targets with their pharmacology, plus links to an open access knowledgebase of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. The full contents can be found at http://onlinelibrary.wiley.com/doi/10.1111/bph.13347/full. This compilation of the major pharmacological targets is divided into eight areas of focus: G protein-coupled receptors, ligand-gated ion channels, voltage-gated ion channels, other 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 Concise Guide is published in landscape format in order to facilitate comparison of related targets. It is a condensed version of material contemporary to late 2015, which is presented in greater detail and constantly updated on the website www.guidetopharmacology.org, superseding data presented in the previous Guides to Receptors & Channels and the Concise Guide to PHARMACOLOGY 2013/14. 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.

Entities: CellLine Chemical Disease Gene Species

Mesh：

Year: 2015 PMID： 26650438 PMCID： PMC4718217 DOI： 10.1111/bph.13347

Source DB: PubMed Journal: Br J Pharmacol ISSN： 0007-1188 Impact factor: 8.739

5729 Overview 5734 Other Protein Targets 5734 Adiponectin receptors 5735 Blood coagulation components 5735 Non‐enzymatic BRD containing proteins 5736 Carrier proteins 5737 CD molecules 5738 Methyllysine reader proteins 5739 Cytokines and growth factors 5739 Fatty acid‐binding proteins 5741 Sigma receptors 5742 Tubulins BPH13348:: 5744 G protein‐coupled receptors 5746 Orphan and other 7TM receptors 5746 Class A Orphans 5756 Class C Orphans 5756Taste 1 receptors 5757 Taste 2 receptors 5758 Other 7TM proteins 5759 5‐Hydroxytryptamine receptors 5764 Acetylcholine receptors (muscarinic) 5766 Adenosine receptors 5768 Adhesion Class GPCRs 5770 Adrenoceptors 5774 Angiotensin receptors 5775 Apelin receptor 5777 Bile acid receptor 5778 Bombesin receptors 5780 Bradykinin receptors 5781 Calcitonin receptors 5783 Calcium‐sensing receptors 5784 Cannabinoid receptors 5785 Chemerin receptor 5785 Chemokine receptors 5791Cholecystokinin receptors 5792Class Frizzled GPCRs 5793 Complement peptide receptors 5795 Corticotropin‐releasing factor receptors 5796 Dopamine receptors 5798 Endothelin receptors 5799 G protein‐coupled estrogen receptor 5800 Formylpeptide receptors 5801 Free fatty acid receptors 5803 GABAB receptors 5805 Galanin receptors 5806 Ghrelin receptor 5807 Glucagon receptor family 5809 Glycoprotein hormone receptors 5810 Gonadotrophin‐releasing hormone receptors 5811 GPR18, GPR55 and GPR119 5812 Histamine receptors 5814 Hydroxycarboxylic acid receptors 5815 Kisspeptin receptor 5816 Leukotriene receptors 5818 Lysophospholipid (LPA) receptors 5819 Lysophospholipid (S1P) receptors 5820 Melanin‐concentrating hormone receptors 5821 Melanocortin receptors 5822 Melatonin receptors 5823 Metabotropic glutamate receptors 5826 Motilin receptor 5827 Neuromedin U receptors 5828 Neuropeptide FF/neuropeptide AF receptors 5829 Neuropeptide S receptor 5828 Neuropeptide W/neuropeptide B receptors 5830 Neuropeptide Y receptors 5832 Neurotensin receptors 5833 Opioid receptors 5835 Orexin receptors 5836 Oxoglutarate receptor 5836 P2Y receptors 5838 Parathyroid hormone receptors 5839 Platelet‐activating factor receptor 5840 Prokineticin receptors 5841 Prolactin‐releasing peptide receptor 5842 Prostanoid receptors 5844 Proteinase‐activated receptors 5844 QRFP receptor 5846 Relaxin family peptide receptors 5848 Somatostatin receptors 5850 Succinate receptor 5850 Tachykinin receptors 5852 Thyrotropin‐releasing hormone receptors 5852 Trace amine receptor 5854 Urotensin receptor 5854 Vasopressin and oxytocin receptors 5856 VIP and PACAP receptors 5870 Ligand‐Gated Ion Channels 5871 5‐HT3 receptors 5873 Acid‐sensing (proton‐gated) ion channels (ASICs) 5875 Epithelial sodium channels (ENaC) 5877 GABAA receptors 5882 Glycine receptors 5885 Ionotropic glutamate receptors 5891 IP3 receptor 5891 Nicotinic acetylcholine receptors 5896 P2X receptors 5898 Ryanodine receptor 5900 ZAC 5904 Voltage‐gated ion channels 5905 CatSper and Two‐Pore channels 5907 Cyclic nucleotide‐regulated channels 5909 Potassium channels 5910 Calcium‐activated potassium channels 5912 Inwardly rectifying potassium channels 5915 Two‐P potassium channels 5917 Voltage‐gated potassium channels 5920 Transient Receptor Potential channels 5934 Voltage‐gated calcium channels 5936 Voltage‐gated proton channel 5937 Voltage‐gated sodium channels 5942 Other ion channels 5943 Aquaporins 5944 Chloride channels 5944 ClC family 5947 CFTR 5948 Calcium activated chloride channel 5949 Maxi chloride channel 5950 Volume regulated chloride channels 5952 Connexins and Pannexins 5954 Sodium leak channel, non‐selective 5956 Nuclear hormone receptors 5958 1A. Thyroid hormone receptors 5959 1B. Retinoic acid receptors 5960 1C. Peroxisome proliferator‐activated receptors 5961 1D. Rev‐Erb receptors 5962 1F. Retinoic acid‐related orphans 5963 1H. Liver X receptor‐like receptors 5964 1I. Vitamin D receptor‐like receptors 5965 2A. Hepatocyte nuclear factor‐4 receptors 5966 2B. Retinoid X receptors 5967 2C. Testicular receptors 5968 2E. Tailless‐like receptors 5969 2F. COUP‐TF‐like receptors 5970 3B. Estrogen‐related receptors 5971 4A. Nerve growth factor IB‐like receptors 5972 5A. Fushi tarazu F1‐like receptors 5973 6A. Germ cell nuclear factor receptors 5974 0B. DAX‐like receptors 5975 Steroid hormone receptors 5975 3A. Estrogen receptors 5976 3C. 3‐Ketosteroid receptors 5979 Catalytic receptors 5981 Cytokine receptor family 5981 IL‐2 receptor family 5983 IL‐3 receptor family 5983 IL‐6 receptor family 5985 IL‐12 receptor family 5985 Prolactin receptor family 5986 Interferon receptor family 5987 IL‐10 receptor family 5988 Immunoglobulin‐like family of IL‐1 receptors 5889 IL‐17 receptor family 5890 GDNF receptor family 5891 Integrins 5994 Natriuretic peptide receptor family 5996 Pattern recognition receptors 5996 Toll‐like receptor family 5997 NOD‐like receptor family 5999 Receptor serine/threonine kinase (RSTK) family 6000 Type I receptor serine/threonine kinases 6001 Type II receptor serine/threonine kinases 6001 Type III receptor serine/threonine kinases 6002 RSTK functional heteromers 6003 Receptor tyrosine kinases 6004 Type I RTKs: ErbB (epidermal growth factor) receptor family 6005 Type II RTKs: Insulin receptor family 6005 Type III RTKs: PDGFR, CSFR, Kit, FLT3 receptor family 6007 Type IV RTKs: VEGF (vascular endothelial growth factor) receptor family 6008 Type V RTKs: FGF (fibroblast growth factor) receptor family 6008 Type VI RTKs: PTK7/CCK4 6009 Type VII RTKs: Neurotrophin receptor/Trk family 6010 Type VIII RTKs: ROR family 6010 Type IX RTKs: MuSK 6010 Type X RTKs: HGF (hepatocyte growth factor) receptor family 6011 Type XI RTKs: TAM (TYRO3‐, AXL‐ and MER‐TK) receptor family 6012 Type XII RTKs: TIE family of angiopoietin receptors 6012 Type XIII RTKs: Ephrin receptor family 6013 Type XIV RTKs: RET 6014 Type XV RTKs: RYK 6014 Type XVI RTKs: DDR (collagen receptor) family 6015 Type XVII RTKs: ROS receptors 6015 Type XVIII RTKs: LMR family 6016 Type XIX RTKs: Leukocyte tyrosine kinase (LTK) receptor family 6016 Type XX RTKs: STYK1 6017 Receptor tyrosine phosphatases (RTP) 6018 Tumour necrosis factor (TNF) receptor family 6024 Enzymes 6028 Protein Kinases (EC 2.7.x.x) 6028 Rho kinase 6029 Protein kinase C (PKC) 6029 Alpha subfamily 6029 Delta subfamily 6030 Eta subfamily 6030 FRAP subfamily 6031 CDK4 subfamily 6031 GSK subfamily 6032 Polo‐like kinase (PLK) family 6032 STE7 family 6033 Abl family 6033 Ack family 6034 Janus kinase (JakA) family 6034 Src family 6035 Tec family 6035 RAF family 6036 Peptidases and proteinases 6036 A1: Pepsin 6037 A22: Presenilin 6037 C14: Caspase 6037 M1: Aminopeptidase N 6038 M2: Angiotensin‐converting (ACE and ACE2) 6038 M10: Matrix metallopeptidase 6039 M12: Astacin/Adamalysin 6039 M28: Aminopeptidase Y 6040 M19: Membrane dipeptidase 6040 S1: Chymotrypsin 6041 T1: Proteasome 6042 S8: Subtilisin 6042 S9: Prolyl oligopeptidase 6042 Acetylcholine turnover 6044 Adenosine turnover 6045 Amino acid hydroxylases 6046 L‐Arginine turnover 6047 Arginase 6047 Arginine:glycine amidinotransferase 6047 Dimethylarginine dimethylaminohydrolases 6048 Nitric oxide synthases 6048 Carboxylases and decarboxylases 6049 Carboxylases 6050 Decarboxylases 6052 Catecholamine turnover 6055 Ceramide turnover 6055 Serine palmitoyltransferase 6056 Ceramide synthase 6057 Sphingolipid ??4‐desaturase 6058 Sphingomyelin synthase 6058 Sphingomyelin phosphodiesterase 6059 Neutral sphingomyelinase coupling factors 6059 Ceramide glucosyltransferase 6060 Acid ceramidase 6060 Neutral ceramidases 6061 Alkaline ceramidases 6061 Ceramide kinase 6062 Chromatin modifying enzymes 6062 2.1.1.‐ Protein arginine N‐methyltransferases 6062 3.5.1.‐ Histone deacetylases (HDACs) 6063 Cyclic nucleotide turnover 6063 Adenylyl cyclases 6064 Soluble guanylyl cyclase 6065 Exchange protein activated by cyclic AMP (Epac) 6066 Phosphodiesterases, 3',5'‐cyclic nucleotide 6069 Cytochrome P450 6069 CYP1 family 6070 CYP2 family 6070 CYP3 family 6071 CYP4 family 6072 CYP5, CYP7 and CYP8 families 6072 CYP11, CYP17, CYP19, CYP20 and CYP21 families 6073 CYP24, CYP26 and CYP27 families 6074 CYP39, CYP46 and CYP51 families 6075 Eicosanoid turnover 6076 Endocannabinoid turnover 6077 Cyclooxygenase 6077 Prostaglandin synthases 6079 Lipoxygenases 6080 Leukotriene and lipoxin metabolism 6081 GABA turnover 6082 Glycerophospholipid turnover 6082 Phosphatidylinositol kinases 6083 1‐phosphatidylinositol 4‐kinase family 6083 Phosphatidylinositol‐4‐phosphate 3‐kinase family 6084 Phosphatidylinositol 3‐kinase family 6084 Phosphatidylinositol‐4,5‐bisphosphate 3‐kinase family 6085 1‐phosphatidylinositol‐3‐phosphate 5‐kinase family Type I PIP kinases (1‐phosphatidylinositol‐4‐phosphate 5‐kinase family) 6086 Type II PIP kinases (1‐phosphatidylinositol‐5‐phosphate 4‐kinase family) 6087 Phosphoinositide‐specific phospholipase C 6088 Phospholipase A2 6089 Phosphatidylcholine‐specific phospholipase D 6090 Lipid phosphate phosphatases 6091 Haem oxygenase 6092 Hydrogen sulphide synthesis 6093 Hydrolases 6093 Inositol phosphate turnover 6094 Inositol 1,4,5‐trisphosphate 3‐kinases 6094 Inositol polyphosphate phosphatases 6094 Inositol monophosphatase 6095 Lanosterol biosynthesis pathway 6097 Nucleoside synthesis and metabolism 6099 Sphingosine 1‐phosphate turnover 6100 Sphingosine kinase 6100 Sphingosine 1‐phosphate phosphatase 6101 Sphingosine 1‐phosphate lyase 6101 Thyroid hormone turnover 6103 1.14.11.29 2‐oxoglutarate oxygenases 6103 2.4.2.30 poly(ADP‐ribose)polymerases 6104 2.5.1.58 Protein farnesyltransferase 6104 3.5.3.15 Peptidyl arginine deiminases (PADI) 6104 RAS subfamily 6105 4.2.1.1 Carbonate dehydratases 6105 5.99.1.2 DNA Topoisomerases 6110 Transporters 6113 ATP‐binding cassette transporter family 6113 ABCA subfamily 6115 ABCB subfamily 6116 ABCC subfamily 6117 ABCD subfamily of peroxisomal ABC transporters 6118 ABCG subfamily 6119 F‐type and V‐type ATPases 6119 F‐type ATPase 6120 V‐type ATPase 6120 P‐type ATPases 6121 Na+/K+‐ATPases 6121 Ca2 +‐ATPases 6122 H+/K+‐ATPases 6122 Cu+‐ATPases 6122 Phospholipid‐transporting ATPases 6123 Major facilitator superfamily (MFS) of transporters 6123 SLC superfamily of solute carriers 6124 SLC1 family of amino acid transporters 6124 Glutamate transporter subfamily 6126 Alanine/serine/cysteine transporter subfamily 6127 SLC2 family of hexose and sugar alcohol 6127 Class I transporters 6128 Class II transporters 6129 Proton‐coupled inositol transporter 6129 SLC3 and SLC7 families of heteromeric amino acid transporters (HATs) 6130 SLC3 family 6130 SLC7 family 6131 SLC4 family of bicarbonate transporters 6132 Anion exchangers 6132 Sodium‐dependent HCO3 transporters 6133 SLC5 family of sodium‐dependent glucose transporters 6134 Hexose transporter family 6135 Choline transporter 6136 Sodium iodide symporter, sodium‐dependent multivitamin transporter and sodium‐coupled monocarboxylate transporters 6137 Sodium myo‐inositol cotransporter transporters 6138 SLC6 neurotransmitter transporter family 6138 Monoamine transporter subfamily 6139 GABA transporter subfamily 6141 Glycine transporter subfamily 6142 Neutral amino acid transporter subfamily 6144 SLC8 family of sodium/calcium exchangers 6145 SLC9 family of sodium/hydrogen exchangers 6145 SLC10 family of sodium‐bile acid co‐transporters 6147 SLC11 family of proton‐coupled metal ion transporters 6148 SLC12 family of cation‐coupled chloride transporters 6149 SLC13 family of sodium‐dependent sulphate/carboxylate transporters 6150 SLC14 family of facilitative urea transporters 6151 SLC15 family of peptide transporters 6152 SLC16 family of monocarboxylate transporters 6154 SLC17 phosphate and organic anion transporter family 6154 Type I sodium‐phosphate co‐transporters 6155 Sialic acid transporter 6155 Vesicular glutamate transporters (VGLUTs) 6156 Vesicular nucleotide transporter 6156 SLC18 family of vesicular amine transporters 6158 SLC19 family of vitamin transporters 6159 SLC20 family of sodium‐dependent phosphate transporters 6160 SLC22 family of organic cation and anion transporters 6160 Organic cation transporters (OCT) 6161 Organic zwitterions/cation transporters (OCTN) 6162 Organic anion transporters (OATs) 6163 Urate transporter 6163 SLC23 family of ascorbic acid transporters 6164 SLC24 family of sodium/potassium/calcium exchangers 6165 SLC25 family of mitochondrial transporters 6165 Mitochondrial di‐ and tri‐carboxylic acid transporter subfamily 6166 Mitochondrial amino acid transporter subfamily 6167 Mitochondrial phosphate transporters 6167 Mitochondrial nucleotide transporter subfamily 6168 Mitochondrial uncoupling proteins 6169 Miscellaneous SLC25 mitochondrial transporters 6170 SLC26 family of anion exchangers 6170 Selective sulphate transporters 6171 Anion channels 6171 Other SLC26 anion exchangers 6172 SLC27 family of fatty acid transporters 6173 SLC28 and SLC29 families of nucleoside transporters 6173 SLC28 family 6174 SLC29 family 6176 SLC30 zinc transporter family 6176 SLC31 family of copper transporters 6177 SLC32 vesicular inhibitory amino acid transporter 6178 SLC33 acetylCoA transporter 6179 SLC34 family of sodium phosphate co‐transporters 6180 SLC35 family of nucleotide sugar transporters 6181 SLC36 family of proton‐coupled amino acid transporters 6182 SLC37 family of phosphosugar/phosphate exchangers 6182 SLC38 family of sodium‐dependent neutral amino acid transporters 6183 System A‐like transporters 6183 System N‐like transporters 6184 Orphan SLC38 transporters 6185 SLC39 family of metal ion transporters 6186 SLC40 iron transporter 6187 SLC41 family of divalent cation transporters 6187 SLC42 family of Rhesus glycoprotein ammonium transporters 6188 SLC43 family of large neutral amino acid transporters 6189 SLC44 choline transporter‐like family 6190 SLC45 family of putative sugar transporters 6191 SLC46 family of folate transporters 6192 SLC47 family ofmultidrug and toxin extrusion transporters 6192 SLC48 heme transporter 6193 SLC49 family of FLVCR‐related heme transporters 6194 SLC50 sugar transporter 6195 SLC51 family of steroid‐derived molecule transporters 6195 SLC52 family of riboflavin transporters 6196 SLCO family of organic anion transporting polypeptides 6199 Patched family

Introduction

In order to allow clarity and consistency in pharmacology, there is a need for a comprehensive organisation and presentation of the targets of drugs. This is the philosophy of the IUPHAR/BPS Guide to PHARMACOLOGY presented on the online free access database (http://www.guidetopharmacology.org/). This database is supported by the British Pharmacological Society (BPS), the International Union of Basic and Clinical Pharmacology (IUPHAR), the Wellcome Trust and the University of Edinburgh. Data included in the Guide to PHARMACOLOGY are derived in large part from interactions with the subcommittees of the Nomenclature Committee of the International Union of Basic and Clinical Pharmacology (NC‐IUPHAR). The Editors of the Concise Guide have compiled the individual records, in concert with the team of Curators, drawing on the expert knowledge of these latter subcommittees. The tables allow an indication of the status of the nomenclature for the group of targets listed, usually previously published in Pharmacological Reviews. In the absence of an established subcommittee, advice from several prominent, independent experts has generally been obtained to produce an authoritative consensus on nomenclature, which attempts to fit in within the general guidelines from NC‐IUPHAR. This current edition, the Concise Guide to PHARMACOLOGY 2015/16, is the latest snapshot of the database in print form, following on from the Concise Guide to PHARMACOLOGY 2013/14. It contains data drawn from the online database as a rapid overview of the major pharmacological targets. Thus, there are fewer targets presented in the Concise Guide (1761) compared to the online database (2761, as of August 2015). The priority for inclusion in the Concise Guide is the presence of quantitative pharmacological data. This means that often orphan family members are not presented in the Concise Guide, although structural information is available on the online database. An expansion in the current version of the Concise Guide is the increased inclusion of approved drugs, which reflects the aim of the online database to reflect the clinical exploitation of human molecular targets. Although many of these agents are much less selective than the tool compounds listed to define individual targets or groups of targets, we have included them for the significant interest associated with their use and mechanisms of action. The emphasis on approved drugs means that the online database has been expanded to include 8024 ligands (as of August 2015), meaning that additional records now appear in the Concise Guide, primarily in the enzymes section. The organisation of the data is tabular (where appropriate) with a standardised format, where possible on a single page, intended to aid understanding of and comparison within a particular target group. The Concise Guide is intended as an initial resource, with links to additional reviews and resources for greater depth and information. Pharmacological and structural data focus primarily on human gene products, wherever possible, with links to HGNC gene nomenclature and UniProt IDs. In a few cases, where data from human proteins are limited, data from other species are indicated. Pharmacological tools listed are prioritised on the basis of selectivity and availability. That is, agents (agonists, antagonists, inhibitors, activators, etc.) are included where they are both available (by donation or from commercial sources, now or in the near future) AND the most selective. This edition of the Concise Guide is divided into nine sections, which comprise pharmacological targets of similar structure/function. These are G protein‐coupled receptors, ligand‐gated ion channels, voltage‐gated ion channels, other ion channels, catalytic receptors, nuclear hormone receptors, enzymes, transporters and other protein targets. A new aspect of the Concise Guide 2015/16 is that each of these sections contains a complete listing of the families available for inspection on the online database, identifying those families reported in the Concise Guide by their page numbers. We hope that the Concise Guide will provide for researchers, teachers and students a state‐of‐the‐art source of accurate, curated information on the background to their work that they will use in the Introductions to their Research Papers or Reviews, or in supporting their teaching and studies. We recommend that any citations to information in the Concise Guide are presented in the following format: Alexander SPH et al. (2015). The Concise Guide to PHARMACOLOGY 2015/16: Overview. Br J Pharmacol XXX. In this overview are listed protein targets of pharmacological interest, which are not G protein‐coupled receptors, ligand‐gated ion channels, voltage‐gated ion channels, ion channels, nuclear hormone receptors, catalytic receptors, transporters or enzymes.

A dedication

This Edition of the Concise Guide to PHARMACOLOGY is dedicated to Tony Harmar (1951‐2014). Tony was a friend and colleague, who was involved with IUPHAR for over 15 years and worked on the IUPHAR database for over a decade at Edinburgh, working hard to establish the curators as a team of highly informed and informative individuals imbued with Tony's passion and dogged determination to focus on high‐quality data input, ensuring high‐quality data output. With time and the resources of the BPS and Wellcome Trust, combined with the expertise of the NC‐IUPHAR committee members mentioned above, Tony established the online database at http://www.guidetopharmacology.org/ as the exceptional resource it is today.

Acknowledgements

We are extremely grateful for the financial contributions from the British Pharmacological Society, the International Union of Basic and Clinical Pharmacology, the Wellcome Trust (099156/Z/12/Z]), which support the website and the University of Edinburgh, who host the guidetopharmacology.org website. We are also tremendously grateful to the long list of collaborators from NC‐IUPHAR subcommittees and beyond, who have assisted in the construction of the Concise Guide to PHARMACOLOGY 2015/16 and the online database www.GuideToPHARMACOLOGY.org.

Conflict of interest

The authors state that there are no conflicts of interest to disclose.

Other Protein Targets

Family structure

5734 Adiponectin receptors ‐ B‐cell lymphoma 2 (Bcl‐2) protein family 5735 Blood coagulation components ‐ Bromodomain‐containing proteins 5735 Non‐enzymatic BRD containing proteins 5736 Carrier proteins 5737 CD molecules ‐ Chromatin‐interacting transcriptional repressors 5738 Methyllysine reader proteins ‐ Circadian clock proteins 5739 Cytokines and growth factors ‐ EF‐hand domain containing 5739 Fatty acid‐binding proteins ‐ Heat shock proteins ‐ Immunoglobulins ‐ Inhibitors of apoptosis (IAP) protein family ‐ Kelch‐like proteins ‐ Kinesins ‐ Mitochondrial‐associated proteins ‐ Notch receptors ‐ Pentaxins ‐ Serum pentaxins ‐ Regulators of G protein signaling (RGS) proteins ‐ RZ family ‐ R4 family ‐ R7 family ‐ R12 family ‐ Reticulons ‐ Ribosomal factors 5741 Sigma receptors 5742 Tubulins ‐ Tumour‐associated proteins ‐ WD repeat‐containing proteins

Adiponectin receptors

Overview

Adiponectin receptors (provisional nomenclature, ENSFM00500000270960) respond to the 30 kDa complement‐related protein hormone adiponectin (also known as : adipocyte, C1q and collagen domain‐containing protein; ACRP30, adipose most abundant gene transcript 1; apM‐1; gelatin‐binding protein: Q15848) originally cloned from adipocytes [49]. Although sequence data suggest 7TM domains, immunological evidence indicates that, contrary to typical 7TM topology, the carboxyl terminus is extracellular, while the amino terminus is intracellular [86]. Signalling through these receptors appears to avoid G proteins. Adiponectin receptors appear rather to stimulate protein phosphorylation via AMP‐activated protein kinase and MAP kinase pathways [86], possibly through the protein partner (adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing 1, Q9UKG1[52]). The adiponectin receptors are a class of proteins (along with membrane progestin receptors), which contain seven sequences of aliphatic amino acids reminiscent of GPCRs, but which are structurally and functionally distinct from that class of receptor.

Comments

T‐Cadherin (, P55290) has also been suggested to be a receptor for (hexameric) adiponectin [35].

Blood coagulation components

Coagulation as a patho/physiological process is interpreted as a mechanism for reducing excessive blood loss through the generation of a gel‐like clot local to the site of injury. The process involves the activation, adhesion (see Integrins), degranulation and aggregation of platelets, as well as proteins circulating in the plasma. The coagulation cascade involves multiple proteins being converted to more active forms from less active precursors, typically through proteolysis (see Proteases). Listed here are the components of the coagulation cascade targetted by agents in current clinical usage. Astermark J (2015) FVIII inhibitors: pathogenesis and avoidance. Blood 125: 2045‐2051 blue[PMID:25712994]

Non‐enzymatic BRD containing proteins

bromodomains bind proteins with acetylated lysine residues, such as histones, to regulate gene transcription. Listed herein are examples of bromodomain‐containing proteins for which sufficient pharmacology exists. Brand M et al. (2015) Small molecule inhibitors of bromodomain‐acetyl‐lysine interactions. ACS Chem Biol 10:22‐39 blue[PMID:25549280] Filippakopoulos P and Knapp S (2014) Targeting bromodomains: epigenetic readers of lysine acetylation. Nat Rev Drug Discov 13: 337‐356 blue[PMID:24751816] Gallenkamp D et al. (2014) Bromodomains and their pharmacological inhibitors. ChemMedChem 9: 438‐464 blue[PMID:24497428] Sanchez R et al. (2014) The bromodomain: from epigenome reader to druggable target. Biochim Biophys Acta 1839: 676‐685 blue[PMID:24686119]

Carrier proteins

TTR is a homo‐tetrameric protein which transports thyroxine in the plasma and cerebrospinal fluid and retinol (vitamin A) in the plasma. Many disease causing mutations in the protein have been reported, many of which cause complex dissociation and protein mis‐assembly and deposition of toxic aggregates amyloid fibril formation [66]. These amyloidogenic mutants are linked to the development of pathological amyloidoses, including familial amyloid polyneuropathy (FAP) [1, 13], familial amyloid cardiomyopathy (FAC) [37], amyloidotic vitreous opacities, carpal tunnel syndrome [57] and others. In old age, non‐mutated TTR can also form pathological amyloid fibrils [85]. Pharmacological intervention to reduce or prevent TTR dissociation is being pursued as a theapeutic strategy. To date one small molecule kinetic stabilising molecule (tafamidis) has been approved for FAP, and is being evaluated in clinical trials for other TTR amyloidoses.

CD molecules

Cluster of differentiation refers to an attempt to catalogue systematically a series of over 300 cell‐surface proteins associated with immunotyping. Many members of the group have identified functions as enzymes (for example, see CD73 ecto‐5'‐nucleotidase) or receptors (for example, see CD41 integrin, alpha 2b subunit). Many CDs are targetted for therapeutic gain using antibodies for the treatment of proliferative disorders. A full listing of all the Clusters of Differentiation is not possible in the Guide to PHARMACOLOGY; listed herein are selected members of the family targetted for therapeutic gain.

Methyllysine reader proteins

Methyllysine reader proteins bind to methylated proteins, such as histones, allowing regulation of gene expression. Liu K et al. (2015) Epigenetic targets and drug discovery Part 2: Histone demethylation and DNA methylation. Pharmacol Ther 151: 121‐140 blue[PMID:25857453] Musselman CA et al. (2014) Towards understanding methyllysine readout. Biochim Biophys Acta 1839: 686‐693 blue[PMID:24727128] Thinnes CC et al. (2014) Targeting histone lysine demethylases ‐ progress, challenges, and the future. Biochim Biophys Acta 1839: 1416‐1432 blue[PMID:24859458]

Cytokines and growth factors

cytokines and growth factors are a group of small proteins released from cells, which act upon the same cell or neighbouring cells, often with a role in immune regulation and/or proliferation. Listed herein are examples of cytokines and growth factors targetted for therapeutic benefit.

Fatty acid‐binding proteins

Fatty acid‐binding proteins are low molecular weight (100‐130 aa) chaperones for long chain fatty acids, fatty acyl CoA esters, eicosanoids, retinols, retinoic acids and related metabolites and are usually regarded as being responsible for allowing the otherwise hydrophobic ligands to be mobile in aqueous media. These binding proteins may perform functions extracellularly (e.g. in plasma) or transport these agents; to the nucleus to interact with nuclear receptors (principally PPARs and retinoic acid receptors [76]) or for interaction with metabolic enzymes. Although sequence homology is limited, crystallographic studies suggest conserved 3D structures across the group of binding proteins. Although not tested at all FABPs, BMS309403 exhibits high affinity for FABP4 (pIC50 8.8) compared to FABP3 or FABP5 (pIC50 <6.6) [20, 81]. HTS01037 is reported to interfere with FABP4 action [31]. Multiple pseudogenes for the FABPs have been identified in the human genome. Chmurzyńska A. (2006) The multigene family of fatty acid‐binding proteins (FABPs): function, structure and polymorphism. J. Appl. Genet. 47: 39‐48 [PMID:16424607] Furuhashi M et al. (2008) Fatty acid‐binding proteins: role in metabolic diseases and potential as drug targets. Nat Rev Drug Discov 7: 489‐503 [PMID:18511927] Kralisch S et al. (2013) Adipocyte fatty acid binding protein: a novel adipokine involved in the pathogenesis of metabolic and vascular disease? Diabetologia 56: 10‐21 [PMID:23052058] Schroeder F et al. (2008) Role of fatty acid binding proteins and long chain fatty acids in modulating nuclear receptors and gene transcription. Lipids 43: 1‐17 [PMID:17882463] Storch J et al. (2010) Tissue‐specific functions in the fatty acid‐binding protein family. J. Biol. Chem. 285: 32679‐83 [PMID:20716527] Yamamoto T et al. (2009) Classification of FABP isoforms and tissues based on quantitative evaluation of transcript levels of these isoforms in various rat tissues. Biotechnol. Lett. 31: 1695‐701 [PMID:19565192]

Sigma receptors

Although termed ‘receptors’, the evidence for coupling through conventional signalling pathways is lacking. Initially described as a subtype of opioid receptors, there is only a modest pharmacological overlap and no structural convergence with the G protein‐coupled receptors. A wide range of compounds, ranging from psychoactive agents to antihistamines, have been observed to bind to these sites, which appear to be intracellular. Dubrovsky B. (2006) Neurosteroids, neuroactive steroids, and symptoms of affective disorders. Pharmacol. Biochem. Behav. 84: 644‐55 [PMID:16962651] Guitart X et al. (2004) Sigma receptors: biology and therapeutic potential. Psychopharmacology (Berl.) 174: 301‐19 [PMID:15197533] Matsumoto RR et al. (2003) Sigma receptors: potential medications development target for anti‐cocaine agents. Eur. J. Pharmacol. 469: 1‐12 [PMID:12782179] de Medina P et al. (2011) Importance of cholesterol and oxysterols metabolism in the pharmacology of tamoxifen and other AEBS ligands. Chem. Phys. Lipids 164: 432‐7 [PMID:21641337]

Tubulins

Tubulins are a family of intracellular proteins most commonly associated with microtubules, part of the cytoskeleton. They are exploited for therapeutic gain in cancer chemotherapy as targets for agents derived from a variety of natural products: taxanes, colchicine and vinca alkaloids. These are thought to act primarily through β‐tubulin, thereby interfering with the normal processes of tubulin polymer formation and disassembly. Kaur R et al. (2014) Recent developments in tubulin polymerization inhibitors: An overview. Eur J Med Chem 87: 89‐124 [PMID:25240869] Lu Y et al. (2012) An overview of tubulin inhibitors that interact with the colchicine binding site. Pharm. Res. 29: 2943‐71 [PMID:22814904] Perdiz D et al. (2011) The ins and outs of tubulin acetylation: more than just a post‐translational modification? Cell. Signal. 23: 763‐71 [PMID:20940043] Schappi JM et al. (2014) Tubulin, actin and heterotrimeric G proteins: coordination of signaling and structure. Biochim. Biophys. Acta 1838: 674‐81 [PMID:24071592] Song Y et al. (2015) Post‐translational modifications of tubulin: pathways to functional diversity of microtubules. Trends Cell Biol. 25: 125‐36 [PMID:25468068] Yu I et al. (2015) Writing and Reading the Tubulin Code. J. Biol. Chem. 290: 17163‐72 [PMID:25957412]

Nomenclature	Adipo1 receptor	Adipo2 receptor
HGNC, UniProt	ADIPOR1, Q96A54	ADIPOR2, Q86V24
Rank order of potency	globular adiponectin (ADIPOQ, Q15848) >adiponectin (ADIPOQ, Q15848)	globular adiponectin (ADIPOQ, Q15848) = adiponectin (ADIPOQ, Q15848)

Nomenclature	coagulation factor V (proaccelerin, labile factor)	coagulation factor VIII, procoagulant component	serpin peptidase inhibitor, clade C (antithrombin), member 1
HGNC, UniProt	F5, P12259	F8, P00451	SERPINC1, P01008
Selective activators	–	–	heparin (pK _d 7.8) [25], fondaparinux (pK _d 7.5) [65], dalteparin [34], danaparoid [15, 58], enoxaparin [17], tinzaparin [19]
Selective antagonists	drotrecogin alfa (Inhibition) [40, 41]	drotrecogin alfa (Inhibition) [40, 41]	–

Nomenclature	bromodomain adjacent to zinc finger domain, 2A	bromodomain adjacent to zinc finger domain, 2B	CREB binding protein	polybromo 1	SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4
HGNC, UniProt	BAZ2A, Q9UIF9	BAZ2B, Q9UIF8	CREBBP, Q92793	PBRM1, Q86U86	SMARCA4, P51532
Selective inhibitors	GSK2801 (pK _d 6.6) 73	GSK2801 (Binding) (pK _d 6.9) 73	I‐CBP112 (pK _d 6.8) 72	PFI‐3 (Binding) (pK _d 7.3) 79	PFI‐3 (Binding) (pK _d 7.1) 79

Nomenclature	transthyretin
Common abreviation	TTR
HGNC, UniProt	TTR, P02766

Nomenclature	CD2	CD3e molecule, epsilon (CD3‐TCR complex)	CD20 (membrane‐spanning 4‐domains, subfamily A, member 1)	CD33	CD52	CD80	CD86	cytotoxic T‐lymphocyte‐associated protein 4 (CD152)
Common abreviation	–	–	–	–	–	–	–	CTLA‐4
HGNC, UniProt	CD2, P06729	CD3E, P07766	MS4A1, P11836	CD33, P20138	CD52, P31358	CD80, P33681	CD86, P42081	CTLA4, P16410
Selective inhibitors	–	–	–	–	–	abatacept [84], belatacept [16]	abatacept [84], belatacept [16]	–
Selective antagonists	alefacept (Inhibition) [56, 89]	–	–	–	–	–	–	–
Antibodies	–	catumaxomab (Binding) [46], muromonab‐CD3 (Binding) [24], otelixizumab (Binding) [7]	ofatumumab (Binding) (pK _d 9.9) 47, rituximab (Binding) (pK _d 8.5) [78], ibritumomab tiuxetan (Binding), obinutuzumab (Binding) [2, 68], tositumomab (Binding)	lintuzumab (Binding) (pK _d∼10) [8], gemtuzumab ozogamicin (Binding) [6]	alemtuzumab (Binding) [22]	–	–	ipilimumab (Binding) (pK _d>9) 28, tremelimumab (Binding) (pK _d 8.9) 30

Nomenclature	programmed cell death 1 (CD279)
Common abreviation	PD‐1
HGNC, UniProt	PDCD1, Q15116
Antibodies	pembrolizumab (Binding) (pK _d∼10) 9, nivolumab (Binding) (pK _d 9.1) [29, 42, 43]
Comments	The endogenous ligands for human PD‐1 are programmed cell death 1 ligand 1 (PD‐L1 aka CD274 (CD274, Q9NZQ7)) and programmed cell death 1 ligand 2 (PD‐L2; PDCD1LG2). These ligands are cell surface peptides, normally involved in immune system regulation. Many types of cancer cells evolve mechanisms to evade control and elimination by the immune system. Such mechanisms can include inhibition of so‐called 'immune checkpoints', which would normally be involved in the maintenance of immune homeostasis. An increasingly important area of clinical oncology research is the development of new agents which impede these evasion techniques, thereby switching immune vigilance back on, and effecting immune destruction of cancer cells. Three molecular targets of checkpoint inhibitors which are being extensively pursued are cytotoxic T‐lymphocyte antigen 4 (CTLA4), programmed cell death 1 (PD‐1), and programmed cell death ligand 1 (PD‐L1). Using antibody‐based therapies targeting these pathways, clinical responses have been reported in various tumour types, including melanoma, renal cell carcinoma [64] and non‐small cell lung cancer [39, 51]. pembrolizumab is the first‐in‐class, anti‐PD‐1 antibody to be approved by the US FDA, with ongoing clinical trials for nivolumab (e.g. NCT01673867, NCT01721746) and pidilizumab (NCT02077959, NCT01952769).

Nomenclature	l(3)mbt‐like 3 (Drosophila)
HGNC, UniProt	L3MBTL3, Q96JM7
Selective agonists	UNC1215 (pK _d 6.9) [38]

Nomenclature	interleukin 1, beta	tumor necrosis factor	vascular endothelial growth factor A
HGNC, UniProt	IL1B, P01584	TNF, P01375	VEGFA, P15692
Antagonists	–	–	aflibercept (Inhibition) [10, 11, 82]
Selective antagonists	–	etanercept (Inhibition) [18, 23]	pegaptanib (Inhibition) [26, 61]
Antibodies	gevokizumab (Binding) (pK _d 12.5) [36, 53, 71], canakinumab (Binding) (pK _d 10.5) 27, rilonacept (Binding) [32, 55]	golimumab (Inhibition) (pIC₅₀ 10.7) [77], infliximab (Inhibition) (pK _d 8.7) 44, adalimumab (Inhibition) (pK _d>8) 75, certolizumab pegol (Inhibition) [60]	ranibizumab (Inhibition) (pK _d∼9.8) 3, bevacizumab (Inhibition) (pIC₅₀ 8–8.3) 3

Nomenclature	fatty acid binding protein 1, liver	fatty acid binding protein 2, intestinal	fatty acid binding protein 3, muscle and heart	fatty acid binding protein 4, adipocyte	fatty acid binding protein 5 (psoriasis‐associated)
HGNC, UniProt	FABP1, P07148	FABP2, P12104	FABP3, P05413	FABP4, P15090	FABP5, Q01469
Rank order of potency	stearic acid, oleic acid>palmitic acid, linoleic acid>arachidonic acid, α‐linolenic acid [69]	stearic acid>palmitic acid,oleic acid>linoleic acid>arachidonic acid, α‐linolenic acid [69]	stearic acid, oleic acid, palmitic acid>linoleic acid, α‐linolenic acid, arachidonic acid [69]	oleic acid, palmitic acid, stearic acid, linoleic acid>α‐linolenic acid, arachidonic acid [69]	–
Comments	A broader substrate specificity than other FABPs, binding two fatty acids per protein [83].	Crystal structure of the rat FABP2 [74].	Crystal structure of the human FABP3 [87].	–	Crystal structure of the human FABP5 [33].

Nomenclature	fatty acid binding protein 6, ileal	fatty acid binding protein 7, brain	peripheral myelin protein 2	fatty acid binding protein 9, testis	fatty acid binding protein 12
HGNC, UniProt	FABP6, P51161	FABP7, O15540	PMP2, P02689	FABP9, Q0Z7S8	FABP12, A6NFH5
Comments	Able to transport bile acids [88].	Crystal structure of the human FABP7 [4].	In silico modelling suggests that FABP8 can bind both fatty acids and cholesterol [50].	–	–

Nomenclature	retinol binding protein 1, cellular	retinol binding protein 2, cellular	retinol binding protein 3, interstitial	retinol binding protein 4, plasma	retinol binding protein 5, cellular
HGNC, UniProt	RBP1, P09455	RBP2, P50120	RBP3, P10745	RBP4, P02753	RBP5, P82980
Rank order of potency	–	stearic acid>palmitic acid, oleic acid, linoleic acid, α‐linolenic acid, arachidonic acid [70]	–	–	–

Nomenclature	retinol binding protein 7, cellular	retinaldehyde binding protein 1	cellular retinoic acid binding protein 1	cellular retinoic acid binding protein 2
HGNC, UniProt	RBP7, Q96R05	RLBP1, P12271	CRABP1, P29762	CRABP2, P29373
Rank order of potency	–	11‐cis‐retinal, 11‐cis‐retinol>9‐cis‐retinal, 13‐cis‐retinal, 13‐cis‐retinol, all‐trans‐retinal, retinol [14]	tretinoin >alitretinoin stearic acid>palmitic acid, oleic acid, linoleic acid, α‐linolenic acid, arachidonic acid [70]	–

Nomenclature	sigma non‐opioid intracellular receptor 1	σ2
HGNC, UniProt	SIGMAR1, Q99720	–
Agonists	–	PB‐28 (pK _i 8.3) [5], 1,3‐ditolylguanidine (pK _i 7.4) [45] – Guinea pig
(Sub)family‐selective agonists	(RS)‐PPCC (pK _i 8.8) [67]	–
Selective agonists	PRE‐084 (pIC₅₀ 7.4) [80], (+)‐SK&F10047	–
Antagonists	(‐)‐pentazocine	SM 21 (pIC₅₀ 7.2) [48]
Selective antagonists	NE‐100 (pIC₅₀ 8.4) [62], BD‐1047 (pIC₅₀ 7.4) [54]	–
Labelled ligands	[³H]pentazocine (Agonist)	[³H]‐di‐o‐tolylguanidine (Agonist)
Comments	–	There is no molecular correlate of the σ2 receptor.

Nomenclature	tubulin, alpha 1a	tubulin, alpha 4a	tubulin, beta class I	tubulin, beta 3 class III	tubulin, beta 4B class IVb	tubulin, beta 8 class VIII
HGNC, UniProt	TUBA1A, Q71U36	TUBA4A, P68366	TUBB, P07437	TUBB3, Q13509	TUBB4B, P68371	TUBB8, Q3ZCM7
Inhibitors	–	–	vinblastine (pIC₅₀ 9), vincristine	–	–	–
(Sub)family‐selective inhibitors	–	–	eribulin (pIC₅₀ 8.2) [59], paclitaxel (Mitotic cell cycle arrest in A431 cells) (pEC₅₀ 8.1) [63], colchicine (pIC₅₀ 8) [12], cabazitaxel, docetaxel, ixabepilone	–	–	–

166 in total

Review 1. The pro-cognitive mechanisms of physical exercise in people with schizophrenia.

Authors: Joseph Firth; Jack Cotter; Rebekah Carney; Alison R Yung
Journal: Br J Pharmacol Date: 2017-04-20 Impact factor: 8.739

2. Biased ligand quantification in drug discovery: from theory to high throughput screening to identify new biased μ opioid receptor agonists.

Authors: David Winpenny; Mellissa Clark; Darren Cawkill
Journal: Br J Pharmacol Date: 2016-03-01 Impact factor: 8.739

Review 10. The therapeutic and diagnostic potential of the prostate specific membrane antigen/glutamate carboxypeptidase II (PSMA/GCPII) in cancer and neurological disease.

Authors: James C Evans; Meenakshi Malhotra; John F Cryan; Caitriona M O'Driscoll
Journal: Br J Pharmacol Date: 2016-09-23 Impact factor: 8.739