The International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR) is a body that issues guidelines for receptor and ion channel classification. It addresses the main issues in pharmacology today, classifying the major receptor and ion channel systems in the human genome and depositing the data on a freely available web site (http://www.iuphar-db.org
). NC-IUPHAR has >50 subcommittees with expert scientists freely giving up their time in order to facilitate the interface between the discovery of new sequences from the Human Genome Project and the designation of the derived proteins as functional receptors and ion channels.
Furthermore, the multitude of factors between a published genomic sequence and an assigned receptor function in a given tissue (epigenetics, alternative splicing, messenger RNA editing, polymorphisms, the combinatorial nature of subunit association) ensures that there are multiple drug targets. The practical implications of the new pharmacology are immense, particularly for drug discovery where the magnitude of the variables affecting drug response is only now becoming fully appreciated. NC-IUPHAR needs input from motivated scientists interested in receptors, so if you are interested please contact us! NC-IUPHAR works in coordination with the Human Genome Organisation (HUGO) Gene Nomenclature Committee (HGNC).
The goals of NC-IUPHAR include: (i) establishing, as far as possible, an overall consistent classification and nomenclature for the LGICs; and (ii) developing a subunit list (with template information for a database). presents such a list of the genes encoding LGIC subunits that are expressed in humans. Thus, certain subunits, such as the nicotinic acetylcholine receptor α8 subunit (Schoepfer et al., 1990
) that has not been identified in the mammalian brain, and the glycine receptor α4 subunit (Matzenbach et al., 1994
), which is likely to be a pseudogene in man, are not listed. Similarly, the avian GABAA
receptor β4 and γ4 subunits, which may have evolved into the mammalian GABAA
receptor θ and ε subunits, respectively, are not tabulated (Simon et al., 2004
). At this point in time we also do not consider intracellular ion channels such as the inositol trisphosphate (IP3
) or ryanodine receptors that are gated by ligands. Other classes of cell surface ion channel that are activated, or modulated, by ligands, such as the cyclic nucleotide regulated ion channels and numerous members of the transient receptor potential family have been the subject of previous NC-IUPHAR recommendations (Clapham et al., 2005
; Hofmann et al., 2005
NC-IUPHAR list of ligand-gated ion channel subunits
In recommending a consistent nomenclature for LGIC subunits, it is appropriate to reflect upon the acceptance, or otherwise, of previous NC-IUPHAR recommendations and current practice in the literature. Lukas et al. (1999)
in an interim NC-IUPHAR statement on the nomenclature of nicotinic acetylcholine receptor subunits stated that ‘the 16 nACh receptor subunits identified to date are defined using a Greek letter sometimes followed by an Arabic numeral (neither subscripted nor superscripted)’. A survey of the literature indicates this formalism to be widely employed. By contrast, in an extensive and still valuable review of the classification of GABAA
receptors, Barnard et al. (1998)
indicated that Greek subunit letters should be followed by a subscripted Arabic numeral, where appropriate. However, a representative search of the literature subsequent to that publication indicates no consistent usage of subscripts even, in some instances, between contributions emanating from the same laboratory. A similar situation is apparent for the strychnine-sensitive glycine receptors, upon which NC-IUPHAR have yet to issue guidance. By contrast, subscripted numbers and letters are almost universally used to denote the 5-HT3
and P2X receptor subunits (e.g. 5-HT3A
) in accordance with previous NC-IUPHAR guidelines (Hoyer et al., 1994
; Khakh et al., 2001
A revised nomenclature of the ionotropic glutamate receptors subunits triggered NC-IUPHAR to reconsider the naming of LGIC subunits in general, but in particular with regard to the use of subscripts. Each of the LGIC subcommittees were consulted in an attempt to reach an overall consensus. Various reasons were elaborated for the continued use (largely historical), or not (consistency across receptor families, reserving subscript to specify receptor stoichiometry, difficulties in database searches, formatting issues) of subscript notation. After considerable deliberation the NC-IUPHAR Committee sets out the following which is a recommendation for implementation:
- The use of subscript may be retained specifically for the receptor names GABAA and 5-HT3. For historical reasons this would be difficult, if not impossible, to change.
- Subunits within a receptor should not be denoted by subscripts.
- Stoichiometry, where known, should be indicated by placing the subunit in parenthesis and indicating the number of subunits by use of a subscripted number following the close of the parenthesis (where the number of subunits is greater than one). This is already a formal recommendation of the NC-IUPHAR nicotinic acetylcholine receptor subcommittee (Lukas et al., 1999). However, stoichiometry should not be indicated unnecessarily.
- Subunits should be listed in alphabetical, or numerical, sequence without punctuation between subunits. An exception arises in the case of subunits types denoted by a numeral (e.g. P2X2; P2X3), where a solidus should be placed between the subunits as previously recommended when describing receptors of unspecified stoichiometry (Khakh et al., 2001).
Examples of the recommended nomenclature are given in and .
NC-IUPHAR recommendations on receptor nomenclature