- Email: [email protected]
Receptor classification and nomenclature: the revolution and the resolution
C
0
Receptor classification and nomenclature: the revolution and the resolution Pat Humphrey,Mike Spedding and Paul Vanhoutte
Ever since Raymond Ahlquisrs landmark observations ~, which led to the now well-accepted concept that cellmembrane receptors for noradrenaline exist in distinct types mediating different functions, pharmacologists have been interested in the characterization of receptors for neurotransmitters and hormones. This approach not only provides explanation of the mechanisms of actions of many drugs but, through the pioneering work of Sir James Black, it is now obvious that rigorous attention to receptor characterization and the identification of selective synthetic ligands can lead to major therapeutic advances. This is exemplified by the introduction of drugs that block f~-adrenoceptors and histamine He receptors 2& Nevertheless, until the advent of modern molecular biology techniques, pharmacologists were sceptical when data from functional studies in whole tissues suggested a multiplicity of receptor types for a given mediator. However, it is now apparent that there are as many as three ~-adrenoceptor types, seven c~-adrenoceptor types, eight prostanoid receptor types and 14 types of receptor for 5-HT (Refs 4-7). This potential for receptor diversity for all neurotransmitters and hormones has now been confirmed by the cloning of many receptor genes and the study of the function of the recombinant receptor proteins for which they code. The speed at which receptor cDNAs are now being cloned has led to a revolutionary situation where new receptor types are being identified before their function in whole tissues, if any, is known. This creates problems for those interested in the classification and nomenclature of receptors. As a consequence of a strong international desire amongst pharmacologists to
© 1904, Elsevier Science 1.td
rationalize the information provided by techniques of molecular biology in relation to drug-related data on receptor function, the Receptor Nomenclature and Drug Classification Committee (NC-IUPHAR) was inaugurated in 1987, under the auspices of the International Union of Pharmacology (IUPHAR). The NC-IUPHAR is now established and endeavouring to provide an open forum for debate on approaches to receptor characterization and to develop guidelines and recommendations for classification and nomenclature. Initial efforts are focused largely on membrane-bound receptors for the common neurotransmitters, but ion channels and other cellular systems involving recognition sites are being considered. Some views on receptor characterization and classification have already been published by the committee s but further effort is being devoted to this by a technical subcommittee, which is also working towards the standardization of terms and symbols used in pharmacology. The technical subcommittee invites input from anyone interested in ligand-receptor theory and works through a panel of distinguished corresponding experts to ensure all views are considered. At the XIIth International Congress of Pharmacology in Montr6al this July, a symposium will be dedicated to the principles of receptor characterization, which will highlight many of the issues for debate. In particular, an integrated pharmacological approach to classification is proposed for appraisal and discussion, which relies on three essential criteria for receptor characterization. These comprise essential data from studies providing structural, operational and transductional
M
M
E
N
T
informationL It is proposed that no single criterion should be considered pre-eminent, although at present, transductional information is limited and its relative importance for definitive characterization of a receptor is as yet unclear and arguably controversial. Operational criteria describe the ligand-related characteristics of a receptor, namely recognitory characteristics towards agonists and antagonists. The term 'operational' has been proposed to refer to the collective interpretation of data from functional (e.g. elevation of cAMP) and ligandreceptor binding studies, both of which provide estimates of ligand affinities. Structural data, while providing definitive identification of distinct proteins, may provide limited information regarding ligand recognition and function of a receptor. Transductional criteria dictate the requirement for information on how each particular receptor produces the triggering of intracellular events on activation. The knowledge of whether a receptor is a ligand-gated ion channel or a G protein-coupled receptor is fundamental, providing critical information regarding receptor identity and function. Beyond this, present understanding of transduction mechanisms is limited, but it is interesting to speculate that each receptor type may have subtly different modes of signalling, for example, each G protein-coupled receptor might recognize different G proteins according to the structure of the intracellular domains of the given receptor m. The NC-IUPHAR symposium programme at the Congress will reflect on these terms and issues, which are being evaluated as working principles for the deliberations of the various subcommittees, most of which are dedicated to the classification of a particular receptor family. There are currently 19 subcommittees whose chairs are appointed by the main NC-IUPHAR committee (Table 1). Each subcommittee chair is expected to appoint the members with guidance, so as to constitute an international working group of experts to provide recommendations
TiPS
July ]994 (Vol.)3)
P. P. A. Humphrey, OilectcJLGL~×cL~sti~ute of A1aphedPha~maco(og,i DepaFtrnepl o~ Pharmacoioqv,mJIliveFsqtV o( Cambridge Tenn,s Court Road Cambridge UK CB2 ~Qs M. Spedding, Research~8rl'[re Dlreuor Insfitut de Recherches Se~ie~ 11 ruedes Mouhneaux,92759 Suresnes, France, and P. M. Vanheutte, vlce-Presicien[ot ReseaFch,Instltut d~ Recherches Imernatiollales Sewier, place des P(6ades, 92415 Courbev~ie France
'~ 0 3
C
o
M
M
E
N
T
Table 1. The Receptor Nomenclature and Drug Classification Subcommittees of the International Union of Pharmacology Subcommittee
Chair
Adrenoceptors Angiotensin receptors Dopamine receptors
S. Z. Langer, Synthelabo, Bagneux M. de Gasparo, Ciba-Geigy, Basel J. C. Schwartz, Institut National de la Sante et de la Recherche Medicale, Centre Paul Broca, Paris I. Masaki, University of Kyoto D. Lodge, Lilly, Windlesham
Endothelin receptors Excitatory amino acid receptors GABAA receptors Histamine receptors 5-HT receptors Imidazoline receptors Leukotriene receptors Muscarinic acetylcholine receptors Opioid receptors Prostanoid receptors Purinoceptors Somatostatin receptors Tachykinin receptors
debate grows and encourages relevant research, a clearer understanding of the nature of cell-membrane receptors should emerge, thus providing a resolution to the problems currently facing pharmacologists who are interested in receptor classification. References
S. Z. Langer, Synthelabo. Bagneux J. P. Green, Mount Sinai School of Medicine, New York G. R. Martin, Wellcome Foundation, Beckenham P. Bousquet, University Louis Pasteur, Strasbourg R. A. Coleman, Glaxo, Ware N. J. M. Birdsall, National Institute of Medical Research, London B. N. Dhawan, Indian Council for Medical Research, Lucknow R. A. Coleman, Glaxo, Ware B. B. Fredholm, Karolinska Institute, Stockholm T. Reisine, University of Pennsylvania R. M. Snider, Burroughs Wellcome, Greenville
Ca2+ channels L-Arginine-NO pathway
R. Paoletti, University of Milan R. F. Furchgott, University of Miami
Technical
P. P. A. Humphrey, Giaxo, Cambridge
on the classification and nomenclature for a given receptor family. Such recommendations must ultimately be sanctioned and authorized by the main committee prior to publication. The prototypical example of such committee reports is the recently published Ca 2÷channel classification documentH. In keeping with these published recommendations, it is not envisaged that early subcommittee deliberations will necessarily be wholly definitive, and extended or even modified classifications are envisaged. They nevertheless pro-
vide an important forum, accessible by the whole pharmacological fraternity for serious debate on the scientific principles and nomenclature issues involved. Full reports will be published to coincide with the Congress, covering the work of the subcommittees on receptors for noradrenaline (c~-adrenoceptors)5, prostanoids ~, 5-HT (Ref. 7), endothelin t2, adenosine and ATP (Refs 13). Other subcommittees will also provide full reports at a later date. As more subcommittees become established and the scientific
1 Ahlquist, R. P. (l~)4g) Am. J. Physiol. 153, 586~00 2 Black, J. W., Duncan, W. A. M., Durant, C. J., Ganellin, C. R. and Parsons, E. M (1972) Nature 236, 38%390 3 Black, J. W. and Prichard, B. N. C. (1973) Br. Med. Bull. 29, 103-167 4 Emorine, L. J. et al. (1991) Bioche,l. Pharmacol. 41,853-85`4 5 Bylund, D. B. et al. (1994) Pharmacol. Re;,. 46, 121-136 6 Coleman, R. A., Smith, W. L. and Narumiya, S. (19'44) Pharmacol. Rev. 46, 205 22`4 7 Hover, D. et al. (lq94) PharmacoL Rez,. 4~, 157~-203 8 Kenakin, T. P., Bond, R. A. and Bonner, T. I. (1992) PharmacoL Rev. 44, 351-362 9 Humphrey, P. P. A., Hartig, P. and Hoyer, D. (1993} Trends Pharmacol. Sci. 14, 233--236 10 Kleuss, C. ct al. (lC~93) Science 259, 832-834 11 Spedding, M. and Paoletti, R. (1992) Pharmacol. Rcv. 44, 363-376 12 Masaki, T., Vane, J. R. and Vanhoutte, P. M (1994) Pharmacol. Rev. 46, 137-142 13 Fredholm, B. B. et al. (1994) Pharmacol. Roy. 46, 143-156
Editor's note
TiPS will publish other articles relating to general issues of receptor characterization in the autumn. Readers are invited to contribute by sending their comments on classification, paTticularly criteria and terminology, in the form of a Letter to the Editor. Correspondence from participants at the symposium mentioned in this article will be welcome.
Pharmacology in Canada This Special Issue was commissioned following visits to Canadian pharmacology laboratories. I am i n d e b t e d to researchers at E d m o n t o n , Calgary, Kingston and McGill for organizing enjoyable d e p a r t m e n t a l visits a n d fruitful discussions, a n d to researchers in Vancouver, Toronto and Montr6al w h o f o u n d time to see me at short notice. ! owe special thanks to Professor Gerald Marks for his advice and enthusiastic support for the project. D. Girdlestone Trends in Pharmacological Sciences
2 0 4
TiPS - J u l y 1994 (Vol. 15)
0
Receptor classification and nomenclature: the revolution and the resolution Pat Humphrey,Mike Spedding and Paul Vanhoutte
Ever since Raymond Ahlquisrs landmark observations ~, which led to the now well-accepted concept that cellmembrane receptors for noradrenaline exist in distinct types mediating different functions, pharmacologists have been interested in the characterization of receptors for neurotransmitters and hormones. This approach not only provides explanation of the mechanisms of actions of many drugs but, through the pioneering work of Sir James Black, it is now obvious that rigorous attention to receptor characterization and the identification of selective synthetic ligands can lead to major therapeutic advances. This is exemplified by the introduction of drugs that block f~-adrenoceptors and histamine He receptors 2& Nevertheless, until the advent of modern molecular biology techniques, pharmacologists were sceptical when data from functional studies in whole tissues suggested a multiplicity of receptor types for a given mediator. However, it is now apparent that there are as many as three ~-adrenoceptor types, seven c~-adrenoceptor types, eight prostanoid receptor types and 14 types of receptor for 5-HT (Refs 4-7). This potential for receptor diversity for all neurotransmitters and hormones has now been confirmed by the cloning of many receptor genes and the study of the function of the recombinant receptor proteins for which they code. The speed at which receptor cDNAs are now being cloned has led to a revolutionary situation where new receptor types are being identified before their function in whole tissues, if any, is known. This creates problems for those interested in the classification and nomenclature of receptors. As a consequence of a strong international desire amongst pharmacologists to
© 1904, Elsevier Science 1.td
rationalize the information provided by techniques of molecular biology in relation to drug-related data on receptor function, the Receptor Nomenclature and Drug Classification Committee (NC-IUPHAR) was inaugurated in 1987, under the auspices of the International Union of Pharmacology (IUPHAR). The NC-IUPHAR is now established and endeavouring to provide an open forum for debate on approaches to receptor characterization and to develop guidelines and recommendations for classification and nomenclature. Initial efforts are focused largely on membrane-bound receptors for the common neurotransmitters, but ion channels and other cellular systems involving recognition sites are being considered. Some views on receptor characterization and classification have already been published by the committee s but further effort is being devoted to this by a technical subcommittee, which is also working towards the standardization of terms and symbols used in pharmacology. The technical subcommittee invites input from anyone interested in ligand-receptor theory and works through a panel of distinguished corresponding experts to ensure all views are considered. At the XIIth International Congress of Pharmacology in Montr6al this July, a symposium will be dedicated to the principles of receptor characterization, which will highlight many of the issues for debate. In particular, an integrated pharmacological approach to classification is proposed for appraisal and discussion, which relies on three essential criteria for receptor characterization. These comprise essential data from studies providing structural, operational and transductional
M
M
E
N
T
informationL It is proposed that no single criterion should be considered pre-eminent, although at present, transductional information is limited and its relative importance for definitive characterization of a receptor is as yet unclear and arguably controversial. Operational criteria describe the ligand-related characteristics of a receptor, namely recognitory characteristics towards agonists and antagonists. The term 'operational' has been proposed to refer to the collective interpretation of data from functional (e.g. elevation of cAMP) and ligandreceptor binding studies, both of which provide estimates of ligand affinities. Structural data, while providing definitive identification of distinct proteins, may provide limited information regarding ligand recognition and function of a receptor. Transductional criteria dictate the requirement for information on how each particular receptor produces the triggering of intracellular events on activation. The knowledge of whether a receptor is a ligand-gated ion channel or a G protein-coupled receptor is fundamental, providing critical information regarding receptor identity and function. Beyond this, present understanding of transduction mechanisms is limited, but it is interesting to speculate that each receptor type may have subtly different modes of signalling, for example, each G protein-coupled receptor might recognize different G proteins according to the structure of the intracellular domains of the given receptor m. The NC-IUPHAR symposium programme at the Congress will reflect on these terms and issues, which are being evaluated as working principles for the deliberations of the various subcommittees, most of which are dedicated to the classification of a particular receptor family. There are currently 19 subcommittees whose chairs are appointed by the main NC-IUPHAR committee (Table 1). Each subcommittee chair is expected to appoint the members with guidance, so as to constitute an international working group of experts to provide recommendations
TiPS
July ]994 (Vol.)3)
P. P. A. Humphrey, OilectcJLGL~×cL~sti~ute of A1aphedPha~maco(og,i DepaFtrnepl o~ Pharmacoioqv,mJIliveFsqtV o( Cambridge Tenn,s Court Road Cambridge UK CB2 ~Qs M. Spedding, Research~8rl'[re Dlreuor Insfitut de Recherches Se~ie~ 11 ruedes Mouhneaux,92759 Suresnes, France, and P. M. Vanheutte, vlce-Presicien[ot ReseaFch,Instltut d~ Recherches Imernatiollales Sewier, place des P(6ades, 92415 Courbev~ie France
'~ 0 3
C
o
M
M
E
N
T
Table 1. The Receptor Nomenclature and Drug Classification Subcommittees of the International Union of Pharmacology Subcommittee
Chair
Adrenoceptors Angiotensin receptors Dopamine receptors
S. Z. Langer, Synthelabo, Bagneux M. de Gasparo, Ciba-Geigy, Basel J. C. Schwartz, Institut National de la Sante et de la Recherche Medicale, Centre Paul Broca, Paris I. Masaki, University of Kyoto D. Lodge, Lilly, Windlesham
Endothelin receptors Excitatory amino acid receptors GABAA receptors Histamine receptors 5-HT receptors Imidazoline receptors Leukotriene receptors Muscarinic acetylcholine receptors Opioid receptors Prostanoid receptors Purinoceptors Somatostatin receptors Tachykinin receptors
debate grows and encourages relevant research, a clearer understanding of the nature of cell-membrane receptors should emerge, thus providing a resolution to the problems currently facing pharmacologists who are interested in receptor classification. References
S. Z. Langer, Synthelabo. Bagneux J. P. Green, Mount Sinai School of Medicine, New York G. R. Martin, Wellcome Foundation, Beckenham P. Bousquet, University Louis Pasteur, Strasbourg R. A. Coleman, Glaxo, Ware N. J. M. Birdsall, National Institute of Medical Research, London B. N. Dhawan, Indian Council for Medical Research, Lucknow R. A. Coleman, Glaxo, Ware B. B. Fredholm, Karolinska Institute, Stockholm T. Reisine, University of Pennsylvania R. M. Snider, Burroughs Wellcome, Greenville
Ca2+ channels L-Arginine-NO pathway
R. Paoletti, University of Milan R. F. Furchgott, University of Miami
Technical
P. P. A. Humphrey, Giaxo, Cambridge
on the classification and nomenclature for a given receptor family. Such recommendations must ultimately be sanctioned and authorized by the main committee prior to publication. The prototypical example of such committee reports is the recently published Ca 2÷channel classification documentH. In keeping with these published recommendations, it is not envisaged that early subcommittee deliberations will necessarily be wholly definitive, and extended or even modified classifications are envisaged. They nevertheless pro-
vide an important forum, accessible by the whole pharmacological fraternity for serious debate on the scientific principles and nomenclature issues involved. Full reports will be published to coincide with the Congress, covering the work of the subcommittees on receptors for noradrenaline (c~-adrenoceptors)5, prostanoids ~, 5-HT (Ref. 7), endothelin t2, adenosine and ATP (Refs 13). Other subcommittees will also provide full reports at a later date. As more subcommittees become established and the scientific
1 Ahlquist, R. P. (l~)4g) Am. J. Physiol. 153, 586~00 2 Black, J. W., Duncan, W. A. M., Durant, C. J., Ganellin, C. R. and Parsons, E. M (1972) Nature 236, 38%390 3 Black, J. W. and Prichard, B. N. C. (1973) Br. Med. Bull. 29, 103-167 4 Emorine, L. J. et al. (1991) Bioche,l. Pharmacol. 41,853-85`4 5 Bylund, D. B. et al. (1994) Pharmacol. Re;,. 46, 121-136 6 Coleman, R. A., Smith, W. L. and Narumiya, S. (19'44) Pharmacol. Rev. 46, 205 22`4 7 Hover, D. et al. (lq94) PharmacoL Rez,. 4~, 157~-203 8 Kenakin, T. P., Bond, R. A. and Bonner, T. I. (1992) PharmacoL Rev. 44, 351-362 9 Humphrey, P. P. A., Hartig, P. and Hoyer, D. (1993} Trends Pharmacol. Sci. 14, 233--236 10 Kleuss, C. ct al. (lC~93) Science 259, 832-834 11 Spedding, M. and Paoletti, R. (1992) Pharmacol. Rcv. 44, 363-376 12 Masaki, T., Vane, J. R. and Vanhoutte, P. M (1994) Pharmacol. Rev. 46, 137-142 13 Fredholm, B. B. et al. (1994) Pharmacol. Roy. 46, 143-156
Editor's note
TiPS will publish other articles relating to general issues of receptor characterization in the autumn. Readers are invited to contribute by sending their comments on classification, paTticularly criteria and terminology, in the form of a Letter to the Editor. Correspondence from participants at the symposium mentioned in this article will be welcome.
Pharmacology in Canada This Special Issue was commissioned following visits to Canadian pharmacology laboratories. I am i n d e b t e d to researchers at E d m o n t o n , Calgary, Kingston and McGill for organizing enjoyable d e p a r t m e n t a l visits a n d fruitful discussions, a n d to researchers in Vancouver, Toronto and Montr6al w h o f o u n d time to see me at short notice. ! owe special thanks to Professor Gerald Marks for his advice and enthusiastic support for the project. D. Girdlestone Trends in Pharmacological Sciences
2 0 4
TiPS - J u l y 1994 (Vol. 15)