one - third of the medicinal drugs in current use and many drugs of abuse target members of three protein superfamilies : nonsensory g protein - coupled receptors ( gpcrs ) , voltage - gated - like ion channels ( vgics ) and ligand - gated ion channels ( lgics ) ( 1 ) .
these proteins , encoded by 570 genes , encompass an estimated 20% of all likely drug targets and are , therefore , a focus of intense research in academia and in industry .
the international union of basic and clinical pharmacology committee on receptor nomenclature and drug classification ( nc - iuphar ; http://www.iuphar.org/nciuphar.html ) has , since 1992 , issued guidelines for receptor and ion channel nomenclature and for classifying the major receptor and ion channel systems .
more recently , an important part of the mission of nc - iuphar has been to facilitate the characterization of new functional receptors and ion channels identified by sequencing of the human , rat and mouse genomes .
in addition to publishing a series of reviews on these issues ( http://www.iuphar.org/nciuphar_arti.html ) , the committee has , since 2000 , worked to create a database of gpcrs and ion channels containing peer - reviewed information on the pharmacology , genetics , function and distribution of these proteins .
gpcrs , also known as seven - transmembrane domain ( 7tm ) receptors because of their characteristic topology , comprise one of the largest protein superfamilies in mammals ( 2 ) and are found in a range of eukaryote taxa .
the binding of extracellular ligands ( e.g. hormones and neurotransmitters ) leads to a conformational change resulting in the activation of intracellular heterotrimeric guanine nucleotide - binding proteins ( g proteins ) which , in turn , regulate numerous signaling pathways including the production or liberation of intracellular second messengers , such as cyclic amp , 1,2-diacylglycerol , inositol 1,4,5-trisphosphate and ca , control of vgic function and assembly of signal - transduction complexes .
gpcrs regulate a wide range of physiological functions , such as hormone secretion , neurotransmitter release , smooth muscle relaxation / contraction , cell apoptosis , immune defense , chemotaxis , cell aggregation , nociception , learning and behavior , neuroplasticity , regulation of sleep - wakefulness cycles and food intake .
nonsensory gpcrs ( i.e. excluding those mediating vision , taste and olfaction ) in humans . of these
orphan receptors , which are proteins that exhibit the characteristic 7tm topology but for which no endogenous ligand has yet been identified .
deorphanisation of these receptors by assigning endogenous ligands and physiological functions to them ( 4 ) .
the vgic superfamily includes 10 families that share a common cation - selective pore - forming module composed of two transmembrane segments and an intervening p loop ( 5 ) .
the voltage - gated na ( nav ) and ca ( cav ) channels are the most structurally complex .
these single ion channel subunits have four repeating domains that each contains six transmembrane segments yielding 24 transmembrane segments in all . in each domain ,
segments s1s4 comprise a regulatory module that confers voltage sensitivity , and segments s5 and s6 and the p loop line the central pore .
in addition to their primary regulation by voltage on the millisecond time scale , these channels have slower secondary regulation by numerous signaling pathways .
members of the two - pore channel family ( tpc ) , whose functional properties are unknown , are composed of two separate subunits that each have two linked domains with six transmembrane segments , similar to the homologous domains of nav and cav channels .
five ion channel families are tetramers of subunits that each has a structure homologous to one domain of a nav or cav channel . voltage - gated k channels ( kv ) are primarily regulated by voltage and secondarily by g proteins and second - messenger signaling pathways .
ca - activated k channels ( kca ) , transient receptor potential channels and hyperpolarization- and cyclic - nucleotide - gated ion channels are jointly regulated by voltage , membrane lipids and intracellular ligands .
cyclic - nucleotide - gated ion channels are primarily regulated by cyclic nucleotides , even though their s1s4 segments are similar in structure to the voltage - gated channels . finally , the two structurally simplest vgics have only pore - forming domains . inwardly rectifying k channels ( kir )
are composed of tetramers of subunits having two transmembrane segments with an intervening p loop .
two - p k channels ( k2p ) are composed of dimers of subunits having two linked pore - forming motifs , each similar to the kir channels .
kir and k2p channels are regulated by membrane lipids and intracellular ligands , including g proteins and small molecules such as mg , polyamines and atp .
diversity within this large protein superfamily is increased by association of the principal pore - forming subunits with one or more auxiliary subunit and by formation of heterooligomers of the pore - forming subunits of the family members that function as tetramers .
lgics , unlike gpcrs , incorporate the ligand - binding site and effector ( i.e. ion channel ) within a common multimeric complex .
they are the mediators of fast , phasic , synaptic transmission in the nervous system and at the skeletal neuromuscular junction .
in addition , some lgics underlie a tonic form of synaptic transmission in the central nervous system and their distribution and functions are not limited to excitable cells .
the lgics form three superfamilies on the basis of homology in the amino acid sequences and topology of their component subunits , namely the pentameric cys - loop , and the cation - selective ionotropic glutamate and p2x receptors , which assemble as tetramers and trimers , respectively .
the cys - loop receptors comprise the cation - selective nicotinic acetylcholine and 5-hydroxytryptamine type-3 ( 5-ht3 ) receptors ( with 17 and 5 subunits , respectively , encoded by distinct genes ) and the anion - selective gabaa ( 19 subunits ) and glycine receptors ( five subunits ) ( 69 ) . a cation - selective zinc - activated channel forms an additional member of the cys - loop superfamily ( 10 ) .
ionotropic glutamate receptors comprise the n - methyl - d - aspartate ( seven subunits ) , -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid ( four subunits ) and kainate ( five subunits ) receptor classes .
the nimh - pdsp ki database ( http://pdsp.med.unc.edu/pdsp.php ) , drugbank ( 13 ) and bindingdb ( 14 ) each contain data on the interaction of small molecule ligands with known or potential drug targets .
pharmgkb ( 15 ) is a pharmacogenetics and pharmacogenomics resource with coverage of many of the drugs and drug targets in iuphar database ( iuphar - db ) .
glida ( gpcr - ligand database ) ( 16 ) contains biological information on gpcrs and chemical information on their known ligands .
gpcrdb ( 17 ) contains cdna and amino acid sequences , multiple sequence alignments , phylogenetic trees and structural models of gpcrs , the gpcr nava database ( 18 ) describes naturally occurring sequence variation in human gpcrs and gpdb ( g protein database ) ( 19 ) is a database of g proteins and their interactions with gpcrs and effector molecules .
the endogenous gpcr list ( http://www.tumor-gene.org/gpcr/ ) tabulates the gpcrs expressed endogenously in various cell lines .
there are two databases of olfactory receptors ( the largest multigene family in multicellular organisms ) : horde ( the human olfactory data explorer ) ( 20 ) and the olfactory receptor database ( 21 ) ; these are sensory gpcrs and are , therefore , outside the scope of iuphar - db .
vkcdb , the voltage - gated potassium channel database ( 22 ) , contains protein sequences and electrophysiological and pharmacological data on voltage - gated potassium channels and lgicdb ( 23 ) contains nucleic acid and protein sequences , multiple sequence alignments , phylogenetic trees and structural information on lgic subunits .
iuphar - db complements existing databases by providing a richly curated overview of the biology of gpcrs and ion channels , underpinned by rigorous peer - review by nc - iuphar and its network of 60 subcommittees of international experts .
iuphar - db is implemented as a mysql relational database ( http://www.mysql.com ) containing information on gpcrs and a postgresql relational database ( http://www.postgresql.org ) holding data on vgics and lgics .
data are submitted and edited using an in - house editing tool written in java and using jdbc to map the biological objects to the database . to ensure that data remain consistent between databases , the editing tool retrieves citations directly from the pubmed database ( http://www.ncbi.nlm.nih.gov/pubmed ) .
the public web interface uses java servlets , java server pages and jdbc to provide free online access to the entire public database .
iuphar - db contains information on the gpcrs , vgics and lgics (  drug targets ) encoded by the human , mouse and rat genomes . in accordance with iuphar guidelines , gpcrs and lgics are grouped into families according to their endogenous ligands ( 24,25 ) , whereas vgics are grouped according to a phylogenetically based classification scheme ( 5 ) .
nc - iuphar has a network of over 60 expert subcommittees , each committee being responsible for developing the nomenclature for their receptor .
the compilation of the data submitted to the database is , in most cases , coordinated by members of the relevant subcommittee . where no relevant subcommittee exists , data are captured by the curators or individual experts and peer reviewed by at least two external expert referees .
data are sourced from and referenced to the primary literature ( original articles in peer - reviewed publications rather than review articles ) , with links to citations in pubmed . wherever possible , data are supported by more than one literature source .
after review by the curators to ensure accuracy and consistency with the rest of the information in the database , the data are added to the production server and transferred to the public database , after approval by nc - iuphar ( updates normally take place twice a year following nc - iuphar executive committee meetings ) .
data are reviewed at regular intervals ( at least yearly ) by subcommittees and other contributors and updated as necessary .
data on each gene in the database can be displayed on an individual page containing the following information : 
 approved iuphar nomenclature alongside alternative or outdated names for the receptor or channel.structural and genomic data linked to its sources in the hugo gene nomenclature committee ( hgnc ) ( 26 ) , mouse genome informatics ( mgi ) ( 27 ) , rat genome ( 28 ) and refseq protein ( 29 ) databases.links to papers describing the first cloning of each receptor or ion channel cdna and gene.links to other databases including entrez gene ( 30 ) , genecards ( 31 ) and omim ( 32 ) . 

the database contains support for heterooligomers composed of two or more gpcr ( 33 ) or ion channel subunits , for example gabab receptor heterodimers ( 34 ) and for complexes of receptors or channels with accessory proteins , for example the multiple pharmacologically distinct receptor subtypes that are generated by association of receptor activity - modifying proteins with the calcitonin - receptor - like receptor and the calcitonin receptor ( 3537 ) . on pages describing such complexes
, there is a subunit table with links to database pages describing the properties of the constituent subunits or accessory proteins .
structural and genomic data linked to its sources in the hugo gene nomenclature committee ( hgnc ) ( 26 ) , mouse genome informatics ( mgi ) ( 27 ) , rat genome ( 28 ) and refseq protein ( 29 ) databases .
links to papers describing the first cloning of each receptor or ion channel cdna and gene .
links to other databases including entrez gene ( 30 ) , genecards ( 31 ) and omim ( 32 ) .
the following curated and peer - reviewed information is provided for all genes in the database ( with the exception , at present , of some orphan gpcrs ) : 
 tissue distribution of gene expression at the levels of mrna , protein and radioligand binding , focusing on the adult.tissue function ( physiological responses mediated by the receptor or ion channel).functional assays ( whole tissue or isolated cell systems in which a pharmacological response can be firmly attributed to the function of a defined receptor or ion channel).physiological consequences of altering gene expression ( e.g. in knockout and transgenic animals).functionally important receptor variants ( e.g. polymorphisms , mutations and splice variants , which have been demonstrated to alter receptor function).tables of affinity data for selected ligands . 

these groups include drugs that are potent and selective and/or used as prescription medications , endogenous ligands ( e.g. 5-ht as an endogenous substance that acts through 5-ht receptors ) and radiolabeled substances that can be employed in radioligand binding studies .
in addition , ligands important for understanding structure  activity relationships for a drug target or a family of receptors or ion channels are included . where possible
, data for these index compounds are included for all members of the receptor or ion channel family .
tissue distribution of gene expression at the levels of mrna , protein and radioligand binding , focusing on the adult .
tissue function ( physiological responses mediated by the receptor or ion channel ) . functional assays ( whole tissue or isolated cell systems in which a pharmacological response can be firmly attributed to the function of a defined receptor or ion channel ) . physiological consequences of altering gene expression ( e.g. in knockout and transgenic animals ) .
functionally important receptor variants ( e.g. polymorphisms , mutations and splice variants , which have been demonstrated to alter receptor function ) .
when possible , the database cites estimates of the equilibrium dissociation constant ( kd ) for each ligand at the cloned human receptor or channel expressed in a transfected cell line , determined in a binding assay using a radiolabeled antagonist as tracer .
when such data are lacking , results obtained from other species and/or from other assay systems are reported .
if possible , data are obtained from more than one publication and a range of values is displayed together with multiple citations .
where available , alternative ligand names are displayed and links are provided to the relevant entry in the pubchem compound database ( 38 ) and to a table listing the potency of the ligand at all other reported receptors and channels in iuphar - db .
tables of ligands can be sorted , for example , alphabetically by name , by activity , by affinity or by the units in which affinity data are provided .
online supplementary figure 1 is an interactive pdf file illustrating the main features of a database page for a gpcr .
these pages contain tables of ligands classified as agonists ( full or partial ) , antagonists , inverse agonists or allosteric regulators ( positive , negative or neutral ) ( 39 ) .
details of primary and secondary transduction mechanisms are given , listing the g proteins involved and the downstream response to receptor activation .
although there is evidence that some vgics may exist as heterooligomeric complexes with distinct pharmacological properties , iuphar - db presently provides information on individual vgic genes and the properties of homomeric channels .
quantitative data are included for the voltage dependence of activation and inactivation , single - channel conductance and binding of drugs and neurotoxins ( classified as activators , gating inhibitors or pore blockers ) , focusing on agents that are widely used and that are diagnostic of channel identity and function . in the case of the lgics , which , in contrast to vgics , do not generally assemble and function as homomers , the characteristics of individual receptors of defined subunit composition are presented .
the data presented comprise entries concerning ion selectivity , conductance and voltage dependence , agonists , antagonists , channel blockers , allosteric regulators and functional assays .
the web interface includes a comprehensive search facility to enable text - based searches of drug targets and ligands .
searches are , by default , across all fields in the database ; alternatively , searches can be focused by selecting one or more fields ( e.g. searching for a receptor name or alias ) .
alphabetical lists of receptor and ion channel families are available via a menu on the page sidebar , which links to individual receptor or channel database pages .
there is an introductory article for each receptor and ion channel family , which reviews the properties , nomenclature and classification of each receptor and channel family .
curated lists of the genes encoding human , mouse and rat gpcrs , vgics and lgics can be viewed as html pages that list the approved iuphar nomenclature , have links to the receptor or channel page in the database , give the name of the primary endogenous ligand or physiological ion , human , rat and mouse gene names and provide links to the entrez gene database for all three species .
alternatively , the gene lists can be downloaded as microsoft excel spreadsheets , which additionally include the hgnc , rgd and mgi identifiers , genomic location , refseq nucleotide and protein accession numbers and swissprot and entrez gene identifiers for human , rat and mouse .
the evolving pharmacology subcommittee of nc - iuphar monitors the literature for reports of new 
pairings of gpcrs with endogenous ligands , for example , the recent emergence of estrogen as an endogenous ligand for gpr30 ( 40 ) .
a  hot topics page ( http://www.iuphar-db.org/hottopics.jsp ) contains brief summaries of important developments in receptor and ion channel pharmacology .
an rss feed ( http://www.iuphar-db.org/feed.xml ) provides details of the latest items added to the database .
the aim of the iuphar - db project is to create a richly annotated resource giving pharmacological , genetic , functional and anatomical information on a subset of drug targets that are of particular importance in the treatment of disease and in the development of new medicines .
uniquely , the content of the database is peer reviewed by international experts and the drug targets are defined unambiguously using iuphar - approved nomenclature .
only drugs that are potent and selective , used clinically or are important in understanding structure  activity relationships are included .
the future development of iuphar - db will include the addition of further classes of drug targets , such as the nuclear receptors ( 41 ) and receptor tyrosine kinases .
refinements to the database will include the provision of more sophisticated search tools and the development of  ligand - centered pages , which will aggregate information on the pharmacology of individual drugs , as an alternative entry point to the database .
although there are other databases that document aspects of the molecular biology and pharmacology of gpcrs and ion channels , iuphar - db is the first in the public domain to integrate curated structural , physiological , pathophysiological and quantitative pharmacological data across a wide range of drug targets .
intended as an international resource for students , scientists and the interested public , the website receives over 3500 unique visitors from 80 countries each month .
british pharmacological society ( through their anniversary strategic initiatives fund ) ; unesco ( through the icsu grants programme ) ; incyte ; glaxosmithkline ; novartis ; servier ; wyeth . funding for open access publication charges
 the iuphar database ( iuphar - db ) integrates peer - reviewed pharmacological , chemical , genetic , functional and anatomical information on the 354 nonsensory g protein - coupled receptors ( gpcrs ) , 71 ligand - gated ion channel subunits and 141 voltage - gated - like ion channel subunits encoded by the human , rat and mouse genomes . 
 these genes represent the targets of approximately one - third of currently approved drugs and are a major focus of drug discovery and development programs in the pharmaceutical industry . 
 iuphar - db provides a comprehensive description of the genes and their functions , with information on protein structure and interactions , ligands , expression patterns , signaling mechanisms , functional assays and biologically important receptor variants ( e.g. single nucleotide polymorphisms and splice variants ) . 
 in addition , the phenotypes resulting from altered gene expression ( e.g. in genetically altered animals or in human genetic disorders ) are described . 
 the content of the database is peer reviewed by members of the international union of basic and clinical pharmacology committee on receptor nomenclature and drug classification ( nc - iuphar ) ; the data are provided through manual curation of the primary literature by a network of over 60 subcommittees of nc - iuphar . 
 links to other bioinformatics resources , such as ncbi , uniprot , hgnc and the rat and mouse genome databases are provided . 
 iuphar - db is freely available at http://www.iuphar-db.org . 
INTRODUCTION
CONSTRUCTION AND CONTENT
ADDITIONAL FILES
DISCUSSION AND FUTURE DIRECTIONS
DATA AVAILABILITY
SUPPLEMENTARY DATA
FUNDING