Stephen Ph Alexander1, Eamonn Kelly2, Neil V Marrion2, John A Peters3, Elena Faccenda4, Simon D Harding4, Adam J Pawson4, Joanna L Sharman4, Christopher Southan4, O Peter Buneman5, John A Cidlowski6, Arthur Christopoulos7, Anthony P Davenport8, Doriano Fabbro9, Michael Spedding10, Jörg Striessnig11, Jamie A Davies4. 1. School of Life Sciences, University of Nottingham Medical School, Nottingham, NG7 2UH, UK. 2. School of Physiology, Pharmacology and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK. 3. Neuroscience Division, Medical Education Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK. 4. Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK. 5. Laboratory for Foundations of Computer Science, School of Informatics, University of Edinburgh, Edinburgh, EH8 9LE, United Kingdom. 6. National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, NC 27709, USA. 7. Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria 3052, Australia. 8. Clinical Pharmacology Unit, University of Cambridge, Cambridge, CB2 0QQ, UK. 9. PIQUR Therapeutics, Basel, 4057, Switzerland. 10. Spedding Research Solutions SARL, Le Vésinet, 78110, France. 11. Pharmacology and Toxicology, Institute of Pharmacy, University of Innsbruck, A-6020 Innsbruck, Austria.
Abstract
The Concise Guide to PHARMACOLOGY 2017/18 is the third in this series of biennial publications. This version provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), 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. Although the Concise Guide represents approximately 400 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/10.1111/bph.13882/full. In addition to this overview, in which are identified 'Other protein targets' which fall outside of the subsequent categorisation, there are 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 landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2017, and supersedes data presented in the 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature Committee of the Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
The Concise Guide to PHARMACOLOGY 2017/18 is the third in this series of biennial publications. This version provides concise overviews of the key properties of nearly 1800 human drug targets with an emphasis on selective pharmacology (where available), 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. Although the Concise Guide represents approximately 400 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/10.1111/bph.13882/full. In addition to this overview, in which are identified 'Other protein targets' which fall outside of the subsequent categorisation, there are 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 landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2017, and supersedes data presented in the 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature Committee of the Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.
S6 Other Protein TargetsS6 Adiponectin receptorsS7 Blood coagulation componentsS8 Non‐enzymatic BRD containing proteinsS8 Carrier proteinsS9 CD moleculesS10 Methyllysine reader proteinsS11 Fatty acid‐binding proteinsS13 Notch receptorsS13 Regulators of G protein Signaling (RGS) proteinsS14 Sigma receptorsS15 TubulinsS17 G protein‐coupled receptorsS19 Orphan and other 7TM receptorsS19 Class A OrphansS28 Class C OrphansS28 Taste 1 receptorsS29 Taste 2 receptorsS30 TM proteinsS31 5‐Hydroxytryptamine receptorsS34 Acetylcholine receptors (muscarinic)S36 Adenosine receptorsS37 Adhesion Class GPCRsS39 AdrenoceptorsS43 Angiotensin receptorsS44 Apelin receptorS45 Bile acid receptorS46 Bombesin receptorsS47 Bradykinin receptorsS48 Calcitonin receptorsS50 Calcium‐sensing receptorS51 Cannabinoid receptorsS52Chemerin receptorS53 Chemokine receptorsS57 Cholecystokinin receptorsS58 Class Frizzled GPCRsS59 Complement peptide receptorsS60 Corticotropin‐releasing factor receptorsS61 Dopamine receptorsS63 Endothelin receptorsS64 G protein‐coupled estrogen receptorS65 Formylpeptide receptorsS66 Free fatty acid receptorsS67 GABA receptorsS69 Galanin receptorsS70 Ghrelin receptorS71 Glucagon receptor familyS72 Glycoprotein hormone receptorsS73 Gonadotrophin‐releasing hormone receptorsS75 GPR18, GPR55 and GPR119S76 Histamine receptorsS77 Hydroxycarboxylic acid receptorsS78 Kisspeptin receptorS79 Leukotriene receptorsS81 Lysophospholipid (LPA) receptorsS82 Lysophospholipid (S1P) receptorsS83 Melanin‐concentrating hormone receptorsS84 Melanocortin receptorsS85 Melatonin receptorsS86 Metabotropic glutamate receptorsS88 Motilin receptorS89 Neuromedin U receptorsS90 Neuropeptide FF/neuropeptide AF receptorsS91 Neuropeptide S receptorS92 Neuropeptide W/neuropeptide B receptorsS93 Neuropeptide Y receptorsS94 Neurotensin receptorsS95 Opioid receptorsS97 Orexin receptorsS98 Oxoglutarate receptorS98 P2Y receptorsS101 Parathyroid hormone receptorsS101 Platelet‐activating factor receptorS102 Prokineticin receptorsS103 Prolactin‐releasing peptide receptorS104 Prostanoid receptorsS106 Proteinase‐activated receptorsS107 QRFP receptorS108 Relaxin family peptide receptorsS110 Somatostatin receptorsS111 Succinate receptorS111 Tachykinin receptorsS113 Thyrotropin‐releasing hormone receptorsS113 Trace amine receptorS114 Urotensin receptorS115 Vasopressin and oxytocin receptorsS117 VIP and PACAP receptorsS130 Ligand‐gated ion channelsS131 5‐HT3 receptorsS133 Acid‐sensing (proton‐gated) ion channels (ASICs)S135 Epithelial sodium channels (ENaC)S137 GABA receptorsS142 Glycine receptorsS145 Ionotropic glutamate receptorsS150 IP3 receptorS151 Nicotinic acetylcholine receptorsS154 P2X receptorsS156 ZACS160 Voltage‐gated ion channelsS161 CatSper and Two‐Pore channelsS163 Cyclic nucleotide‐regulated channelsS164 Potassium channelsS165 Calcium‐ and sodium‐activated potassium channelsS166 Inwardly rectifying potassium channelsS169 Two P domain potassium channelsS171 Voltage‐gated potassium channelsS175 Ryanodine receptorS176 Transient Receptor Potential channelsS186 Voltage‐gated calcium channelsS189 Voltage‐gated proton channelS190 Voltage‐gated sodium channelsS195 Other ion channelsS196 AquaporinsS197 Chloride channelsS197 ClC familyS199 CFTRS200 Calcium activated chloride channelS201 Maxi chloride channelS202 Volume regulated chloride channelsS204 Connexins and PannexinsS206 Sodium leak channel, non‐selectiveS208 Nuclear hormone receptorsS209 1A. Thyroid hormone receptorsS210 1B. Retinoic acid receptorsS210 1C. Peroxisome proliferator‐activated receptorsS211 1D. Rev‐Erb receptorsS212 1F. Retinoic acid‐related orphansS213 1H. Liver X receptor‐like receptorsS214 1I. Vitamin D receptor‐like receptorsS214 2A. Hepatocyte nuclear factor‐4 receptorsS215 2B. Retinoid X receptorsS216 2C. Testicular receptorsS216 2E. Tailless‐like receptorsS217 2F. COUP‐TF‐like receptorsS218 3B. Estrogen‐related receptorsS218 4A. Nerve growth factor IB‐like receptorsS219 5A. Fushi tarazu F1‐like receptorsS220 6A. Germ cell nuclear factor receptorsS220 0B. DAX‐like receptorsS221 Steroid hormone receptorsS221 3A. Estrogen receptorsS222 3C. 3‐Ketosteroid receptorsS225 Catalytic receptorsS226 Cytokine receptor familyS227 IL‐2 receptor familyS229 IL‐3 receptor familyS230 IL‐6 receptor familyS231 IL‐12 receptor familyS232 Prolactin receptor familyS233 Interferon receptor familyS234 IL‐10 receptor familyS235 Immunoglobulin‐like family of IL‐1 receptorsS236 IL‐17 receptor familyS237 GDNF receptor familyS237 IntegrinsS241 Natriuretic peptide receptor familyS242 Pattern recognition receptorsS243 Toll‐like receptor familyS244 NOD‐like receptor familyS246 Receptor tyrosine kinases (RTKs)S247 Type I RTKs: ErbB (epidermal growth factor) receptor familyS248 Type II RTKs: Insulin receptor familyS249 Type III RTKs: PDGFR, CSFR, Kit, FLT3 receptor familyS250 Type IV RTKs: VEGF (vascular endothelial growth factor) receptor familyS251 Type V RTKs: FGF (fibroblast growth factor) receptor familyS252 Type VI RTKs: PTK7/CCK4S252 Type VII RTKs: Neurotrophin receptor/Trk familyS253 Type VIII RTKs: ROR familyS254 Type IX RTKs: MuSKS254 Type X RTKs: HGF (hepatocyte growth factor) receptor familyS255 Type XI RTKs: TAM (TYRO3‐, AXL‐ and MER‐TK) receptor familyS255 Type XII RTKs: TIE family of angiopoietin receptorsS256 Type XIII RTKs: Ephrin receptor familyS257 Type XIV RTKs: RETS257 Type XV RTKs: RYKS258 Type XVI RTKs: DDR (collagen receptor) familyS258 Type XVII RTKs: ROS receptorsS259 Type XVIII RTKs: LMR familyS259 Type XIX RTKs: Leukocyte tyrosine kinase (LTK) receptor familyS260 Type XX RTKs: STYK1S260 Receptor serine/threonine kinase (RSTK) familyS261 Type I receptor serine/threonine kinasesS262 Type II receptor serine/threonine kinasesS262 Type III receptor serine/threonine kinasesS262 RSTK functional heteromersS264 Receptor tyrosine phosphatase (RTP) familyS266 Tumour necrosis factor (TNF) receptor familyS272 EnzymesS275 Kinases (EC 2.7.x.x)S276 Rho kinaseS276 Protein kinase C (PKC)S277 Alpha subfamilyS277 Delta subfamilyS278 Eta subfamilyS278 FRAP subfamilyS279 Cyclin‐dependent kinase (CDK) familyS279 CDK4 subfamilyS279 GSK subfamilyS280 Polo‐like kinase (PLK) familyS280 STE7 familyS281 Abl familyS281 Ack familyS281 Janus kinase (JakA) familyS282 Src familyS283 Tec familyS283 RAF familyS284 Peptidases and proteinasesS284 A1: PepsinS284 A22: PresenilinS285 C14: CaspaseS285 M1: Aminopeptidase NS285 M2: Angiotensin‐converting (ACE and ACE2)S286 M10: Matrix metallopeptidaseS286 M12: Astacin/AdamalysinS287 M28: Aminopeptidase YS287 M19: Membrane dipeptidaseS288 S1: ChymotrypsinS288 T1: ProteasomeS289 S8: SubtilisinS289 S9: Prolyl oligopeptidaseS290 Acetylcholine turnoverS291 Adenosine turnoverS292 Amino acid hydroxylasesS293 L‐Arginine turnoverS294 2.1.1.‐ Protein arginine N‐methyltransferasesS294 ArginaseS294 Arginine:glycine amidinotransferaseS295 Dimethylarginine dimethylaminohydrolasesS295 Nitric oxide synthasesS296 Carboxylases and decarboxylasesS297 CarboxylasesS298 DecarboxylasesS300 Catecholamine turnoverS302 Ceramide turnoverS303 Serine palmitoyltransferaseS303 Ceramide synthaseS304 Sphingolipid Δ4‐desaturaseS304 Sphingomyelin synthaseS305 Sphingomyelin phosphodiesteraseS305 Neutral sphingomyelinase coupling factorsS306 Ceramide glucosyltransferaseS306 Acid ceramidaseS307 Neutral ceramidasesS307 Alkaline ceramidasesS308 Ceramide kinaseS309 Chromatin modifying enzymesS309 2.1.1.‐ Protein arginine N‐methyltransferasesS310 3.5.1.‐ Histone deacetylases (HDACs)S310 Cyclic nucleotide turnover/signallingS310 Adenylyl cyclases (ACs)S312 Exchange protein activated by cyclic AMP (EPACs)S312Nitric oxide (NO)‐sensitive (soluble) guanylyl cyclaseS313 Phosphodiesterases, 3',5'‐cyclic nucleotide (PDEs)S317 Cytochrome P450S317 CYP1 familyS318 CYP2 familyS318 CYP3 familyS319 CYP4 familyS320 CYP5, CYP7 and CYP8 familiesS320 CYP11, CYP17, CYP19, CYP20 and CYP21 familiesS321 CYP24, CYP26 and CYP27 familiesS322 CYP39, CYP46 and CYP51 familiesS323 Endocannabinoid turnoverS323 N‐Acylethanolamine turnoverS324 2‐Acylglycerol ester turnoverS325 Eicosanoid turnoverS325 CyclooxygenaseS326 Prostaglandin synthasesS327 LipoxygenasesS328 Leukotriene and lipoxin metabolismS329 GABA turnoverS331 Glycerophospholipid turnoverS331 Phosphoinositide‐specific phospholipase CS332 Phospholipase A2S334 Phosphatidylcholine‐specific phospholipase DS335 Lipidphosphate phosphatasesS335 Phosphatidylinositol kinasesS336 1‐phosphatidylinositol 4‐kinase familyS336 Phosphatidylinositol‐4‐phosphate 3‐kinase familyS337 Phosphatidylinositol 3‐kinase familyS337 Phosphatidylinositol‐4,5‐bisphosphate 3‐kinase familyS338 1‐phosphatidylinositol‐3‐phosphate 5‐kinase familyS338 Type I PIP kinases (1‐phosphatidylinositol‐4‐phosphate 5‐kinase family)S339 Type II PIP kinases (1‐phosphatidylinositol‐5‐phosphate 4‐kinase family)S339 Haem oxygenaseS340 Hydrogen sulphide synthesisS341 HydrolasesS342 Inositol phosphate turnoverS342 Inositol 1,4,5‐trisphosphate 3‐kinasesS343 Inositol polyphosphate phosphatasesS343 Inositol monophosphataseS344 Lanosterol biosynthesis pathwayS346 Nucleoside synthesis and metabolismS347 Sphingosine 1‐phosphate turnoverS348 Sphingosine kinaseS348 Sphingosine 1‐phosphate phosphataseS349 Sphingosine 1‐phosphate lyaseS349 Thyroid hormone turnoverS350 1.14.11.29 2‐oxoglutarate oxygenasesS351 1.14.13.9 kynurenine 3‐monooxygenaseS352 2.4.2.30 poly(ADP‐ribose)polymerasesS352 2.5.1.58 Protein farnesyltransferaseS353 3.5.1.‐ Histone deacetylases (HDACs)S354 3.5.3.15 Peptidyl arginine deiminases (PADI)S354 RAS subfamilyS355 4.2.1.1 Carbonate dehydratasesS355 5.99.1.2 DNA TopoisomerasesS360 TransportersS362 ATP‐binding cassette transporter familyS362 ABCA subfamilyS363 ABCB subfamilyS365 ABCC subfamilyS366 ABCD subfamily of peroxisomal ABC transportersS367 ABCG subfamilyS368 F‐type and V‐type ATPasesS368 F‐type ATPaseS368 V‐type ATPaseS369 P‐type ATPasesS369 Na+/K+‐ATPasesS369 Ca2+‐ATPasesS370 H+/K+‐ATPasesS370 Cu+‐ATPasesS370 Phospholipid‐transporting ATPasesS371 Major facilitator superfamily (MFS) of transportersS371 SLC superfamily of solute carriersS372 SLC1 family of amino acid transportersS372 Glutamate transporter subfamilyS374 Alanine/serine/cysteine transporter subfamilyS375 SLC2 family of hexose and sugar alcoholS375 Class I transportersS376 Class II transportersS377 Proton‐coupled inositol transporterS377 SLC3 and SLC7 families of heteromeric amino acid transporters (HATs)S377 SLC3 familyS378 SLC7 familyS379 SLC4 family of bicarbonate transportersS380 Anion exchangersS380 Sodium‐dependent HCO
transportersS381 SLC5 family of sodium‐dependent glucose transportersS381 Hexose transporter familyS382 Choline transporterS383 Sodium iodide symporter, sodium‐dependent multivitamin transporter and sodium‐coupled monocarboxylate trans‐ portersS384 Sodium myo‐inositol cotransporter transportersS385 SLC6 neurotransmitter transporter familyS385 Monoamine transporter subfamilyS386 GABA transporter subfamilyS387 Glycine transporter subfamilyS389 Neutral amino acid transporter subfamilyS390 SLC8 family of sodium/calcium exchangersS390 SLC9 family of sodium/hydrogen exchangersS391 SLC10 family of sodium‐bile acid co‐transportersS392 SLC11 family of proton‐coupled metal ion transportersS393 SLC12 family of cation‐coupled chloride transportersS395 SLC13 family of sodium‐dependent sulphate/carboxylate transportersS395 SLC14 family of facilitative urea transportersS396 SLC15 family of peptide transportersS398 SLC16 family of monocarboxylate transportersS399 SLC17 phosphate and organic anion transporter familyS399 Type I sodium‐phosphate co‐transportersS400 Sialic acid transporterS400 Vesicular glutamate transporters (VGLUTs)S401 Vesicular nucleotide transporterS401 SLC18 family of vesicular amine transportersS403 SLC19 family of vitamin transportersS403 SLC20 family of sodium‐dependent phosphate transportersS404 SLC22 family of organic cation and anion transportersS404 Organic cation transporters (OCT)S405 Organic zwitterions/cation transporters (OCTN)S406 Organic anion transporters (OATs)S407 Urate transporterS407 SLC23 family of ascorbic acid transportersS409 SLC24 family of sodium/potassium/calcium exchangersS409 SLC25 family of mitochondrial transportersS410 Mitochondrial di‐ and tri‐carboxylic acid transporter subfamilyS411 Mitochondrial amino acid transporter subfamilyS412 Mitochondrial phosphate transportersS412 Mitochondrial nucleotide transporter subfamilyS413 Mitochondrial uncoupling proteinsS414 Miscellaneous SLC25 mitochondrial transportersS414 SLC26 family of anion exchangersS415 Selective sulphate transportersS415 Chloride/bicarbonate exchangersS416 Anion channelsS416 Other SLC26 anion exchangersS417 SLC27 family of fatty acid transportersS418 SLC28 and SLC29 families of nucleoside transportersS418 SLC28 familyS419 SLC29 familyS420 SLC30 zinc transporter familyS421 SLC31 family of copper transportersS422 SLC32 vesicular inhibitory amino acid transporterS422 SLC33 acetylCoA transporterS423 SLC34 family of sodiumphosphate co‐transportersS424 SLC35 family of nucleotide sugar transportersS425 SLC36 family of proton‐coupled amino acid transportersS426 SLC37 family of phosphosugar/phosphate exchangersS427 SLC38 family of sodium‐dependent neutral amino acid transportersS427 System A‐like transportersS428 System N‐like transportersS428 Orphan SLC38 transportersS429 SLC39 family of metal ion transportersS430 SLC40 iron transporterS430 SLC41 family of divalent cation transportersS431 SLC42 family of Rhesus glycoprotein ammonium transportersS432 SLC43 family of large neutral amino acid transportersS433 SLC44 choline transporter‐like familyS433 SLC45 family of putative sugar transportersS434 SLC46 family of folate transportersS435 SLC47 family of multidrug and toxin extrusion transportersS436 SLC48 heme transporterS436 SLC49 family of FLVCR‐related heme transportersS437 SLC50 sugar transporterS438 SLC51 family of steroid‐derived molecule transportersS438 SLC52 family of riboflavin transportersS439 SLCO family of organic anion transporting polypeptidesS442 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 University of Edinburgh and previously the Wellcome Trust. 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). A major influence on the development of the database was Tony Harmar (1951‐2014), who worked with a passion to establish the curators as a team of highly informed and informative individuals, with a focus on high‐quality data input, ensuring a suitably validated dataset. 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 2017/18, is the latest snapshot of the database in print form, following on from the Concise Guide to PHARMACOLOGY 2015/16. It contains data drawn from the online database as a rapid overview of the major pharmacological targets. Thus, there are many fewer targets presented in the Concise Guide compared to the online database. 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. 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. 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. 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. (2017). The Concise Guide to PHARMACOLOGY 2017/18: Overview. Br J Pharmacol 174: S1–S16.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.
Acknowledgements
We are extremely grateful to the British Pharmacological Society and the International Union of Basic and Clinical Pharmacology, for financial support of the website and for advice from the NC‐IUPHAR subcommittees. We thank the University of Edinburgh, who host the www.guidetopharmacology.org website. Previously, the International Union of Basic and Clinical Pharmacology and the Wellcome Trust (099156/Z/12/Z]) also supported the initiation and expansion of the database. 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 2017/18 and the online database www.GuideToPHARMACOLOGY.org. Further, we wish to thank Toni Wigglesworth for her assistance in the co‐ordination of correspondence with these collaborators.
Conflict of interest
The authors state that there are no conflicts of interest to disclose.
Adiponectin receptors (provisional nomenclature, ENSFM00500000270960) respond to the 30 kDa complement‐related protein hormone adiponectin (also known as ADIPOQ: 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 [90]. Signalling through these receptors appears to avoid G proteins; modelling based on the crystal structures of the adiponectin receptors suggested ceramidase acivity, which would make these the first in a new family of catalytic receptors [93].
Comments
T‐Cadherin (CDH13, P55290) has also been suggested to be a receptor for (hexameric) adiponectin [33].
Further reading on Adiponectin receptors
Fisman EZ et al. (2014) Adiponectin: a manifold therapeutic target for metabolic syndrome, diabetes, and coronary disease? Cardiovasc Diabetol 13: 103 [PMID:24957699]Matsuda M et al. (2014) Roles of adiponectin and oxidative stress in obesity‐associated metabolic and cardiovascular diseases. Rev Endocr Metab Disord 15: 1‐10 [PMID:24026768]Ruan H et al. (2016) Adiponectin signaling and function in insulin target tissues. J Mol Cell Biol 8: 101‐9 [PMID:26993044]Wang Y et al. (2017) Cardiovascular Adiponectin Resistance: The Critical Role of Adiponectin Receptor Modification. Trends Endocrinol Metab 28: 519‐530 [PMID:28473178]Zhao L et al. (2014) Adiponectin and insulin cross talk: the microvascular connection. Trends Cardiovasc Med 24: 319‐24 [PMID:25220977]
Blood coagulation components
Coagulation as a 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.
Further reading on Blood coagulation components
Astermark J. (2015) FVIII inhibitors: pathogenesis and avoidance. Blood 125: 2045‐51 [PMID:25712994]Girolami A et al. (2017) New clotting disorders that cast new light on blood coagulation and may play a role in clinical practice. J Thromb Thrombolysis 44: 71‐75 [PMID:28251495]Rana K et al. (2016) Blood flow and mass transfer regulation of coagulation. Blood Rev 30: 357‐68 [PMID:27133256]
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.
Further reading on Non‐enzymatic BRD containing proteins
Brand M et al. (2015) Small molecule inhibitors of bromodomain‐acetyl‐lysine interactions. ACS Chem. Biol. 10: 22‐39 [PMID:25549280]Fujisawa T et al. (2017) Functions of bromodomain‐containing proteins and their roles in homeostasis and cancer Nat Rev Mol Cell Biol 18: 246‐262 [PMID:28053347]Nicholas DA et al. (2017) BET bromodomain proteins and epigenetic regulation of inflammation: implications for type 2 diabetes and breast cancer. Cell Mol Life Sci 74: 231‐243 [PMID:27491296]Theodoulou NH et al. (2016) Clinical progress and pharmacology of small molecule bromodomain inhibitors. Curr Opin Chem Biol 33: 58‐66 [PMID:27295577]Theodoulou NH et al. (2016) Progress in the Development of non‐BET Bromodomain Chemical Probes. ChemMedChem 11: 477‐87 [PMID:26749027]
Carrier proteins
Transthyretin (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 [63]. These amyloidogenic mutants are linked to the development of pathological amyloidoses, including familial amyloid polyneuropathy (FAP) [4, 14], familial amyloid cardiomyopathy (FAC) [34], amyloidotic vitreous opacities, carpal tunnel syndrome [54] and others. In old age, non‐mutated TTR can also form pathological amyloid fibrils [88]. 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.
Further reading on Carrier proteins
Alshehri B et al. (2015) The diversity of mechanisms influenced by transthyretin in neurobiology: development, disease and endocrine disruption. J Neuroendocrinol 27: 303‐23 [PMID:25737004]Delliere S et al. (2017) Is transthyretin a good marker of nutritional status? Clin Nutr 36: 364‐370 [PMID:27381508]Galant NJ et al. (2017) Transthyretinamyloidosis: an under‐recognized neuropathy and cardiomyopathy. Clin Sci (Lond) 131: 395‐409 [PMID:28213611]
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.
Comment
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. Expression of PD‐1 by cancer cells induces immune tolerance and evasion of immune system attack. Anti‐PD‐1 monoclonal antibodies are used to induce immune checkpoint blockade as a therapeutic intervention in cancer, effectively re‐establishing immune vigilance. pembrolizumab was the first anti‐PD‐1 antibody to be approved by the US FDA.
Further reading on CD molecules
Gabius HJ et al. (2015) The glycobiology of the CD system: a dictionary for translating marker designations into glycan/lectin structure and function. Trends Biochem Sci 40: 360‐76 [PMID:25981696]
Methyllysine reader proteins
Methyllysine reader proteins bind to methylated proteins, such as histones, allowing regulation of gene expression.
Further reading on Methyllysine reader proteins
Liu K et al. (2015) Epigenetic targets and drug discovery Part 2: Histone demethylation and DNA methylation. Pharmacol. Ther. 151: 121‐40 [PMID:25857453]Milosevich N et al. (2016) Chemical Inhibitors of Epigenetic Methyllysine Reader Proteins. Biochemistry 55: 1570‐83 [PMID:26650180]Sadakierska‐Chudy A et al. (2015) A comprehensive view of the epigenetic landscape part I: DNA methylation, passive and active DNA demethylation pathways and histone variants. Neurotox Res 27: 84‐97 [PMID:25362550]Teske KA et al. (2017) Methyllysine binding domains: Structural insight and small molecule probe development. Eur J Med Chem 136: 14‐35 [PMID:28478342]Zahnow CA et al. (2016) Inhibitors of DNA Methylation, Histone Deacetylation, and Histone Demethylation: A Perfect Combination for Cancer Therapy. Adv Cancer Res 130: 55‐111 [PMID:27037751]
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 [70]) 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) [21, 81]. HTS01037 is reported to interfere with FABP4 action [30]. Ibuprofen displays some selectivity for FABP4 (pIC50 5.5) relative to FABP3 (pIC50 3.5) and FABP5 (pIC50 3.8) [48]. Fenofibric acid displays some selectivity for FABP5 (pIC50 5.5) relative to FABP3 (pIC50 4.5) and FABP4 (pIC50 4.6) [48]. Multiple pseudogenes for the FABPs have been identified in the human genome.
Further reading on Fatty acid‐binding proteins
Gajda AM et al. (2015) Enterocyte fatty acid‐binding proteins (FABPs): different functions of liver and intestinal FABPs in the intestine. Prostaglandins Leukot. Essent. Fatty Acids 93: 9‐16 [PMID:25458898]Glatz JF. (2015) Lipids and lipid binding proteins: a perfect match. Prostaglandins Leukot. Essent. Fatty Acids 93: 45‐9 [PMID:25154384]Hotamisligil GS et al. (2015) Metabolic functions of FABPs‐mechanisms and therapeutic implications. Nat Rev Endocrinol 11: 592‐605 [PMID:26260145]Matsumata M et al. (2016) Fatty acid binding proteins and the nervous system: Their impact on mental conditions. Neurosci. Res. 102: 47‐55 [PMID:25205626]Osumi T et al. (2016) Heart lipid droplets and lipid droplet‐binding proteins: Biochemistry, physiology, and pathology. Exp Cell Res 340: 198‐204 [PMID:26524506]
Notch receptors
The canonocal Notch signalling pathway has four type I transmembrane Notch receptors (Notch1‐4) and five ligands (DLL1, 2 and 3, and Jagged 1‐2). Each member of this highly conserved receptor family plays a unique role in cell‐fate determination during embryogenesis, differentiation, tissue patterning, proliferation and cell death [2]. As the Notch ligands are also membrane bound, cells have to be in close proximity for receptor‐ligand interactions to occur. Cleavage of the intracellular domain (ICD) of activated Notch receptors by γ‐secretase is required for downstream signalling and Notch‐induced transcriptional modulation [18, 57, 71, 89]. This is why γ‐secretase inhibitors can be used to downregulate Notch signalling and explains their anti‐cancer action. One such small molecule is RO4929097[47], although development of this compound has been terminated following an unsuccessful Phase II single agent clinical trial in metastatic colorectal cancer [78].Aberrant Notch signalling is implicated in a number of humancancers [41, 59, 74, 85]. Pharmaceutical inhibitors of Notch signalling such as demcizumab and tarextumab are being actively investigated as novel anti‐cancer agents [64].
Further reading on Notch receptors
Borggrefe T et al. (2016) The Notch intracellular domain integrates signals from Wnt, Hedgehog, TGFbeta/BMP and hypoxia pathways. Biochim Biophys Acta 1863: 303‐313 [PMID:26592459]Cheng YL et al. (2015) Emerging roles of the gamma‐secretase‐notch axis in inflammation. Pharmacol Ther 147: 80‐90 [PMID:25448038]Palmer WH et al. (2015) Ligand‐Independent Mechanisms of Notch Activity. Trends Cell Biol 25: 697‐707 [PMID:26437585]Previs RA et al. (2015) Molecular pathways: translational and therapeutic implications of the Notch signaling pathway in cancer. Clin Cancer Res 21: 955‐61 [PMID:25388163]Takebe N et al. (2015) Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat Rev Clin Oncol 12: 445‐464 [PMID:25850553]
Regulators of G protein Signaling (RGS) proteins
Regulators of G protein signalling (RGS) proteins increase the deactivation rates of G protein signalling pathways through enhancing the GTPase activity of the G protein alpha subunit. Interactions through protein:protein interactions of many RGS proteins have been identified for targets other than heteromeric G proteins. The 20 RGS proteins are commonly divided into four families (R4, R7, R12 and RZ) based on sequence and domain homology. Described here is RGS4 for which a number of pharmacological inhibitors have been described.
Further reading on RGS proteins
Sethakorn N et al. (2010) Non‐canonical functions of RGS proteins. Cell Signal 22: 1274‐81 [PMID:20363320]Sjogren B (2017) The evolution of regulators of G protein signalling proteins as drug targets ‐ 20 years in the making: IUPHAR Review 21. Br J Pharmacol 174: 427‐437 [PMID:28098342]Sjogren B et al. (2010) Thinking outside of the "RGS box": new approaches to therapeutic targeting of regulators of G protein signaling. Mol Pharmacol 78: 550‐7 [PMID:20664002]Turner EM et al. (2012) Small Molecule Inhibitors of Regulator of G Protein Signalling (RGS) Proteins. ACS Med Chem Lett 3: 146‐150 [PMID:22368763]
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; the crystal structure of the sigma1 receptor [94] suggests a trimeric structure of a single short transmembrane domain traversing the endoplasmic reticulum membrane, with the bulk of the protein facing the cytosol. A wide range of compounds, ranging from psychoactive agents to antihistamines, have been observed to bind to these sites.(‐)‐pentazocine also shows activity at opioid receptors. The sigma2 receptor has recently been reported to be TMEM97 Q5BJF2[92] , a 4TM protein partner of NPC1, the Niemann‐Pick C1 protein, a 13TM cholesterol‐binding protein.
Further reading on Sigma receptors
Chu UB et al. (2016) Biochemical Pharmacology of the Sigma‐1 Receptor. Mol Pharmacol 89: 142‐53 [PMID:26560551]Gris G et al. (2015) Sigma‐1 receptor and inflammatory pain. Inflamm Res 64: 377‐81 [PMID:25902777]Rousseaux CG et al. (2015) Sigma receptors [sigmaRs]: biology in normal and diseased states. J Recept Signal Transduct Res 1‐62 [PMID:26056947]Su TP et al. (2016) The Sigma‐1 Receptor as a Pluripotent Modulator in Living Systems. Trends Pharmacol Sci 37: 262‐78 [PMID:26869505]van Waarde A et al. (2015) Potential applications for sigma receptor ligands in cancer diagnosis and therapy. Biochim Biophys Acta 1848: 2703‐14 [PMID:25173780]
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.
Further reading on Tubulins
Gadadhar S et al. (2017) The tubulin code at a glance. J Cell Sci 130: 1347‐1353Penna LS et al. (2017) Anti‐mitotic agents: Are they emerging molecules for cancer treatment? Pharmacol Ther 173: 67‐82 [PMID:28174095]
Various types of activating and inactivating NOTCH1 mutations have been reported to be associated with human diseases, for example: aortic valve disease [23, 52], Adams‐Oliver syndrome 5 [76], T‐cell acute lymphoblastic leukemia (T‐ALL) [87], chronic lymphocytic leukemia (CLL) [65] and head and neck squamous cell carcinoma [1, 77].
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Notch 4 is a potential therapeutic molecular target for triple‐negative breast cancer [42, 55].
Authors: Stephen Ph Alexander; Eamonn Kelly; Neil V Marrion; John A Peters; Elena Faccenda; Simon D Harding; Adam J Pawson; Joanna L Sharman; Christopher Southan; O Peter Buneman; John A Cidlowski; Arthur Christopoulos; Anthony P Davenport; Doriano Fabbro; Michael Spedding; Jörg Striessnig; Jamie A Davies Journal: Br J Pharmacol Date: 2017-12 Impact factor: 8.739
Authors: Liliana Raimundo; Margarida Espadinha; Joana Soares; Joana B Loureiro; Marco G Alves; Maria M M Santos; Lucília Saraiva Journal: Br J Pharmacol Date: 2018-09-06 Impact factor: 8.739