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Review ArticleReview

International Union of Pharmacology. XIX. The IUPHAR Receptor Code: A Proposal for an Alphanumeric Classification System

P. P. A. Humphrey and E. A. Barnard
Pharmacological Reviews June 1998, 50 (2) 271-278;
P. P. A. Humphrey
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E. A. Barnard
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    Table 1

    Subdivisions within a complete receptor code

    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
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    Table 9

    Species codes9-a

    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).

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    Table 10

    Splice variant codes10-a

    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.

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    Table 2

    Main structural class codes

    Code          Structural class2-a
    1.0Ion-channel receptors
    2.0Seven transmembrane domain (G protein-coupled)  receptors
    3.0Enzyme-associated receptors (with subunits having one  membrane-inserted domain)
    4.0Transcriptional 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.

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    Table 3

    Subclasses within structural class 1

     CodeSubclassExamples
    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 receptors1.2GLU
    1.3 Related to voltage-gated cation channels
    Includes receptors for cyclic nucleotides and for IP3 as well as the “ryanodine receptor”3-a 1.3IP3
    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)1.4NUCT
    1.5 Related to epithelial Na+channels; peptide-gated
    e.g., FMRF-gated Na+channel (Lingueglia et al., 1995)1.5FMRF
    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 1.6NUCT
    1.73-b Related to ATPase-linked transporters
    e.g., CFTR (ATP-activated anion channel) (Baukrowvitz et al., 1994)3-d 1.7NUCT
    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 1.8GLU

    (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).

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    Table 4

    Subclasses within structural class 2

     CodeSubclassExamples
    2.1 “Rhodopsin” subclass
    The vast majority of seven transmembrane domain, G protein-coupled receptors are included in this subclass4-a 2.1ADR
    2.2 Secretin receptor subclass
    This is the second largest subclass and2.2SEC
     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 2.2CGRP
    2.3 Metabotropic glutamate/GABAB receptor subclass 2.3GLU

    (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).

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    Table 5

    Subclasses within structural class 3

     CodeSubclassExamples
    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 cleavage3.1
    3.1
    3.1
    PDGF
    EGF
    INS
    Trk receptors for neurotrophins3.1NT1
    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
    NTN
    3.3 Receptors with serine/threonine kinase activity
    e.g., receptors for transforming growth factor β3.3TGF
    3.4 Intrinsic cyclase receptors
    e.g., receptors with guanylate cyclase activity3.4ANP

    (enzyme-associated single transmembrane domain receptors)

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    Table 6

    Subclasses within structural class 4

    CodeSubclassExamples
    4.1 Nonsteroid receptors
    This subclass comprises the heterodimeric receptors for nonsteroid ligands including retinoic acid, thyroid hormone, and vitamin D4.1TH VITD3
    4.2 Steroid receptors
    This subclass comprises the homodimeric receptors for steroids including cortisone, aldosterone, progesterone, and testosterone4.2PROG

    (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.

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    Table 7

    Family codes7-a

    AcetylcholineACHMelatoninMLT
    AdenosineADONerve growth factorNGF
    Adenosine and uridine triphosphatesNUCTNeurokininsNK
    AngiotensinANGNeuropeptide YNPY
    Atrial natriuretic peptideANPNeurotrophinsNT1 (etc)
    Hydroxy leukotrienesBLTNeurotensinNTSN
    BradykininBKNeurturinNTN
    CalcitoninCALCNorepinephrine/epinephrineADR
    CannabinoidsCBDOlfactoryOLF
    CholecystokininCCKOpioidsOP
    Calcitonin gene related peptideCGRPOxytocinOXY
    Cysteinyl leukotrienesCLTPituitary adenylate cyclase activating peptidePACAP
    Ciliary neurotrophic factorCNTFPlatelet derived growth factorPDGF
    DopamineDAProgesteronePROG
    Epithelial-derived growth factorEGFProstaglandinsPG
    EndothelinsETSecretinSEC
    γ-Aminobutyric acidGABASerotonin (5-hydroxytryptamine)5HT
    Glial-derived nerve factorGDNFSomatostatinSRIF
    GlutamateGLUTransforming growth factor βTGF
    GlycineGLYThrombinTHR
    Growth hormoneGHThyroid hormoneTH
    GustatoryGUSThyrotropinTSH
    HistamineHISTVasopressinVASO
    InterleukinsIL, IL1 (etc)Vasoactive intestinal polypeptideVIP
    InsulinINSVitamin D3VITD3
    Inositol 1,4,5-trisphosphateIP3
    • ↵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.

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    Table 8

    Receptor type codes

    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.

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International Union of Pharmacology. XIX. The IUPHAR Receptor Code: A Proposal for an Alphanumeric Classification System

P. P. A. Humphrey and E. A. Barnard
Pharmacological Reviews June 1, 1998, 50 (2) 271-278;

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International Union of Pharmacology. XIX. The IUPHAR Receptor Code: A Proposal for an Alphanumeric Classification System

P. P. A. Humphrey and E. A. Barnard
Pharmacological Reviews June 1, 1998, 50 (2) 271-278;
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    • I. Rationale for a Receptor Code
    • II. Criteria for Receptor Characterization
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