Article Figures & Data
Tables
Structural class 1.1–4.4 Indicated by first two numbers; see tables 2-6 for description of associated codes. Receptor family Alphanumeric code (up to six upper case characters, but An endogenous agonist (or family of agonists) provides the receptor family code; see table 7 for recommended codes. usually three) to be used (e.g., 5HT for 5-hydroxytryptamine or serotonin) Receptor type Alphanumeric code (up to five upper case characters) See table 8 for examples. consistent with the approved trivial name or number and its associated recognition and transduction characteristics Species Three upper case letters will code for species as used by See table 9. the Human Genome Database project Splice or other sequence variant 00–99 Pair of numbers after species code; see table 10. Extra category 00–99 Pair of numbers after splice variant code. This is reserved for further subclassification purposes if considered desirable in the future. Where this and the preceding subdivision are not assigned, the zeros can be omitted for most purposes. Final letter code .P, provisional RC (see text) Single upper case letter preceded by a dot. .S, receptor subunit .M, multimeric receptor of known composition BBO Bos bovinus (cow) CAE Cercopithecus aethiops (African green monkey) CFA Canis familiaris (dog) CGR Cricetulus griseus (hamster) CJA Callithrix jacchus (marmoset) CPO Cavia porcellus (guinea-pig) FCA Felis catus (cat) HSA Homo sapiens (man) MML Macaca mulatta (Rhesus monkey) MMU Mus musculus (mouse) MPU Mustela putorius furo(ferret) MRU Macropus rufus (red kangaroo) OCU Oryctolagus cuniculus (rabbit) OOV Ovies ovies (sheep) PPA Papio papio (baboon) PPY Pongo pygmaeus (orangutan) PTR Pan troglodytes (chimpanzee) RNO Rattus norvegicus (rat) SSC Sus scrofa (pig) -
↵9-a These abbreviations are proposed to establish and maintain consistency with existing internationally authoritative nomenclature databases (e.g., GDB, MEDLINE). Alternative abbreviations to denote the species when using trivial receptor names have been published by NC-IUPHAR, and these are still appropriate for use in textual discussion referring to trivial names (see Vanhoutte et al., 1996).
-
It is proposed that the splice variants will be numbered chronologically according to identification within a species, e.g., EP3receptors for prostaglandins (Coleman et al., 1994;Narumiya, 1996) can be coded as: 2.1.PG.EP3.HSA.01 2.1.PG.EP3.HSA.02 2.1.PG.EP3.HSA.03 2.1.PG.EP3.HSA.04 2.1.PG.EP3.OCU.01, etc. Splice variants for a given receptor may have been identified in one species but not in others, e.g., two mouse splice variants have been demonstrated unequivocally for the somatostatin sst2 receptor but not for the human orthologue (Vanetti et al., 1993;Schindler et al., 1996). They can be coded as: 2.1.SRIF.1A.HSA.00 2.1.SRIF.1A.MMU.01 2.1.SRIF.1A.MMU.02 -
↵10-a No code for trinucleotide repeats is recommended; these can be described in the text associated with the relevant RC.
-
Code Structural class2-a 1.0 Ion-channel receptors 2.0 Seven transmembrane domain (G protein-coupled) receptors 3.0 Enzyme-associated receptors (with subunits having one membrane-inserted domain) 4.0 Transcriptional regulator receptors -
↵2-a Each main receptor structure class is subdivided as outlined in Tables 3-6. If the subclass is not known definitively, the main class only will be identified as 1.0, 2.0, etc. These classes are provisional, and additional classes and subclasses may need to be added as knowledge increases. Literature references on receptors in many of the subclasses listed can be found in The IUPHAR Compendium of Receptor Characterization and Classification.
-
Code Subclass Examples 1.1 Superfamily of Cys-loop receptors (Cockcroft et al., 1990;Karlin and Akabas, 1995) Includes ion channels gated by GABA, glycine, 5-HT, acetylcholine (nicotinic), and glutamate (anion channel) (Nistri and Arenson, 1983; Cully et al., 1994,1996) 1.1 1.1 1.1 1.1 1.1 GABA GLY GLU ACH 5HT 1.2 Glutamate-gated cation channels Includes NMDA and non-NMDA receptors 1.2 GLU 1.3 Related to voltage-gated cation channels Includes receptors for cyclic nucleotides and for IP3 as well as the “ryanodine receptor”3-a 1.3 IP3 1.4 Related to epithelial Na+ channels; non-peptide–gated Includes P2X receptors for ATP (North and Barnard, 1997) and proton-gated cation channels (Waldmann et al., 1997) 1.4 NUCT 1.5 Related to epithelial Na+channels; peptide-gated e.g., FMRF-gated Na+channel (Lingueglia et al., 1995) 1.5 FMRF 1.63-b Related to inward rectifier K+channels e.g., ATP-activated K+ channel (Lesageet al., 1995; Takumi et al., 1995) and the ATP-antagonized K+ channel (K ATP) (Clement et al., 1997; Gribble et al., 1997;Tucker et al., 1997)3-c 1.6 NUCT 1.73-b Related to ATPase-linked transporters e.g., CFTR (ATP-activated anion channel) (Baukrowvitz et al., 1994)3-d 1.7 NUCT 1.83-b Related to neurotransmitter transporters e.g., glutamate-activated chloride channel/EAA transporter (Fairman et al., 1995; Picaud et al., 1995)3-d 1.8 GLU (ion-channel receptors)
-
↵3-a It should be noted that subclass 1.3 will contain at least two protein superfamilies, which do not share any sequence homology. One comprises the cyclic nucleotide receptors and the second comprises the IP3 and the ryanodine receptors.
-
↵3-b It is recognized that the definition of subclasses 1.6, 1.7, and 1.8 may require modification as knowledge of them increases, but they serve to illustrate the full potential of the proposed coding system.
-
↵3-c Several KATP channel subtypes are known in different tissues, differing greatly in their response to inhibitory sulfonyl ureas (SUR) and to channel-opening drugs such as diazoxide. Their structures, as known so far by DNA cloning, contain two unrelated subunits, an inward rectifier K+ channel protein (from the Kir.6 series) and a sulfonylurea- and nucleotide-binding protein (SUR); a family of SURs produce variations in the KATPpharmacology (Inagaki et al., 1996). Therefore,KATP channel subunits will be numbered in two series; for the KIR (6.1), etc., subunits as 1.6.KIR.61.S [or 62.S, etc.] and for the SUR1, etc., subunits 1.6.SUR.01.S [or 02.S etc.], and the entire KATP channel as 1.6.NUCT.01.M [or 02.M, etc.] when definitive evidence for the subunit composition is known.
-
↵3-d Although genes for types 1.7 and 1.8 have each been cloned, expressed, and shown to correspond to channels seen in native tissues (Baukrowvitz et al., 1994; Fairman et al., 1995), the precise relationship of the ion channel to the transporter in these types is at present unclear. Transporters are not necessarily ligand-gated channels: however, in addition to the case of glutamate transporters, transporters of serotonin (5-HT) and of dopamine incorporate, respectively, a 5-HT-gated channel (Galli et al., 1997) or a dopamine-gated channel (Sonders et al., 1997), and this principle may hold also for norepinephrine and γ-aminobutyric acid transporters (Sonders and Amara, 1996).
-
Code Subclass Examples 2.1 “Rhodopsin” subclass The vast majority of seven transmembrane domain, G protein-coupled receptors are included in this subclass4-a 2.1 ADR 2.2 Secretin receptor subclass This is the second largest subclass and 2.2 SEC comprises receptors for calcitonin, CGRP, corticotropin-releasing factor, gastric inhibitory peptide, glucagon, glucagon-like peptide, growth hormone releasing factor, PACAP, parathyroid hormone, secretin and vasoactive intestinal peptide 2.2 CGRP 2.3 Metabotropic glutamate/GABAB receptor subclass 2.3 GLU (G protein-coupled receptors)
-
The subclasses shown have been classified according to their protein sequences so that within a subclass all receptor types share significant similarity (i.e., ≥20% sequence identity) throughout the predicted hydrophobic transmembrane domains (Kolakowski, 1994; see also the G protein-Coupled Receptor Database at www.gcrdb.ulthscsa.edu).
-
↵4-a From the strict structural viewpoint, Class 2.1 is not homogeneous. All its members comprise a seven-transmembrane amino acid chain, but in a very few, the active receptor is formed from this by a proteolytic cleavage. The first described was the thrombin receptor (2.1.THR), in which the agonist thrombin specifically cleaves the receptor chain to liberate a new N-terminal segment and activate the receptor (Vu et al., 1991). Others are the thyrotropin receptor (2.1.TSH), where a peptidase produces two extracellular chains (Misrahi et al., 1994), and other protease-activated receptors where the natural agonist is an unidentified trypsin-like protease (Nystedt et al., 1995; Ishihara et al., 1997).
-
Code Subclass Examples 3.1 Receptors with intrinsic tyrosine kinase (TK) activity e.g., single-subunit TK receptors with extracellular Ig domains; single-subunit TK receptors without extracellular Ig domains; multiple-subunit TK receptors formed by posttranslational cleavage 3.1
3.1
3.1
PDGF
EGF
INS
Trk receptors for neurotrophins 3.1 NT1 3.2 Non-enzyme–containing receptors associating with extrinsic tyrosine kinase This includes a wide range of receptor types including: (a) receptors that use JAK-type kinases; (b) receptors that associate with other tyrosine kinases, and (c) tyrosine-kinase-associated receptors with the ligand-binding subunit membrane anchored by a glycolipid, such as that for ciliary neurotrophic factor. These receptors are multisubunit, with a ligand-specific α subunit and a subunit type for signal transduction (for examples see Jing et al., 1996; Kleinet al., 1997) 3.2
3.2
3.2
3.2
3.2
3.2
IL1
GH
INF
CNTF
GDNF
NTN3.3 Receptors with serine/threonine kinase activity e.g., receptors for transforming growth factor β 3.3 TGF 3.4 Intrinsic cyclase receptors e.g., receptors with guanylate cyclase activity 3.4 ANP (enzyme-associated single transmembrane domain receptors)
Code Subclass Examples 4.1 Nonsteroid receptors This subclass comprises the heterodimeric receptors for nonsteroid ligands including retinoic acid, thyroid hormone, and vitamin D 4.1 TH VITD3 4.2 Steroid receptors This subclass comprises the homodimeric receptors for steroids including cortisone, aldosterone, progesterone, and testosterone 4.2 PROG (transcriptional regulator receptors)
-
Nuclear receptors constitute a distinctive class which has great therapeutic relevance but recently has been overlooked somewhat by pharmacologists. With the discovery of multiple orphan nuclear receptors and hence of other potential structural subclasses (seeKastner et al., 1995; Mangelsdorf et al., 1995; Laudet et al., 1998), we suggest that effort should be applied to further subclassification of this class on the basis of the integrated pharmacological approach proposed here.
-
Acetylcholine ACH Melatonin MLT Adenosine ADO Nerve growth factor NGF Adenosine and uridine triphosphates NUCT Neurokinins NK Angiotensin ANG Neuropeptide Y NPY Atrial natriuretic peptide ANP Neurotrophins NT1 (etc) Hydroxy leukotrienes BLT Neurotensin NTSN Bradykinin BK Neurturin NTN Calcitonin CALC Norepinephrine/epinephrine ADR Cannabinoids CBD Olfactory OLF Cholecystokinin CCK Opioids OP Calcitonin gene related peptide CGRP Oxytocin OXY Cysteinyl leukotrienes CLT Pituitary adenylate cyclase activating peptide PACAP Ciliary neurotrophic factor CNTF Platelet derived growth factor PDGF Dopamine DA Progesterone PROG Epithelial-derived growth factor EGF Prostaglandins PG Endothelins ET Secretin SEC γ-Aminobutyric acid GABA Serotonin (5-hydroxytryptamine) 5HT Glial-derived nerve factor GDNF Somatostatin SRIF Glutamate GLU Transforming growth factor β TGF Glycine GLY Thrombin THR Growth hormone GH Thyroid hormone TH Gustatory GUS Thyrotropin TSH Histamine HIST Vasopressin VASO Interleukins IL, IL1 (etc) Vasoactive intestinal polypeptide VIP Insulin INS Vitamin D3 VITD3 Inositol 1,4,5-trisphosphate IP3 -
↵7-a This list is not exhaustive but represents receptor families for which classifications are well developed and a few illustrations of newer receptor families that are not well classified.
-
1. For well established classifications, the receptor type category will be represented by an upper case alphanumeric code that is recognizable as analogous to the trivial nomenclature, e.g., for the G protein-coupled serotonin receptors (see Hoyer et al., 1994; Eglen et al.,1997): 2.1.5HT.01A. for the 5-HT1A receptor 2.1.5HT.01B. for the 5-HT1B receptor 2.1.5HT.01D. for the 5-HT1D receptor 2.1.5HT.02A. for the 5-HT2A receptor 2.1.5HT.07. for the 5-HT7 receptor, etc. 2.1.ADR.A1A. for the α1A adrenoceptor 2.1.ADR.B1. for the β1 adrenoceptor, etc. 2. Where subclassification has not been attempted, a simple chronological numeric code may be assigned, although this approach seems scientifically parsimonious and circumvents an opportunity to provide additional classifying information (e.g., as for dopamine receptors; see Humphrey, 1998).8-a 2.1.DA.01. 2.1.DA.02., etc. The use of an alphanumeric abbreviation for the receptor type category would allow either for recognizable reference to trivial names or direct reference for more recently identified receptors to the simple numbering system used by molecular biologists. Parenthetically, it is suggested that in some cases, for example the muscarinic acetylcholine and dopamine receptor families, consideration should be given as to whether the latter current schemes are still appropriate (see Humphrey, 1997). Regardless, the two options for designating an RC are outlined below and each subcommittee could choose one for their receptor family.
-
↵8-a It is recognized that there is a view strongly held by some that an arbitrary numeric code should be used for all receptor types, which would circumvent past problems associated with incorrectly assigning trivial names. However, after much discussion at NC-IUPHAR meetings, it was agreed that many pharmacologists would not readily accept a system which, for example, groups together the adrenoceptor family without distinguishing between alpha and beta types, with their very different pharmacological characteristics. Nevertheless, if consistent yet arbitrary numeric codes were considered desirable in the future, it would be simple to number each receptor type according to its established position in the database.
-