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Receptors for diadenosine polyphosphates P2D, P2YApnA, P4 and dinucleotide receptors: are there too many?
LETTERS
Receptors for diadenosine polyphosphates P2D, P2YApnA, P4 and dinucleotide receptors: are there too many? In 1993, we described the existence of binding sites for diadenosine polyphosphates in the CNS, which we termed P2D receptors, that have a strikingly high affinity for adenine dinucleotides1. Since then, several papers have used this nomenclature (P2D) and other terms (e.g. P2YApnA , P4 and dinucleotide receptor) to define specific receptors for these compounds. Part of this seemingly random and imprecise nomenclature rests on three basic points: (1) an inadequate interpretation of the binding data; (2) the effort of the IUPHAR to include this receptor within the P2X, P2Y nomenclature as a result of the evident structural analogy of dinucleotides to mononucleotides; and (3) the discovery of a specific receptor for diadenosine polyphosphates. In addition, it is important to remember that diadenosine polyphosphates can stimulate both P2X and P2Y receptors in various tissues, and heterologously expressed receptors2,3. The name P2D was coined according to radioligand binding studies and was not based on functional studies so it cannot be considered as a true receptor. It is just a binding site. The IUPHAR committee changed the name P2D to P2YApnA to fit this binding site within one of the two P2X (ligand-gated ion channels) and P2Y (G-protein-coupled) receptor families4. Nevertheless, the lack of functional studies suggests that there is no reason to include the P2D binding site as a P2Y receptor (P2YApnA) because
functional studies regarding its signal transduction mechanism have never been reported. Recently, evidence for a metabotropic dinucleotide receptor that regulates ATP responses in astrocytes with affinity in the nanomolar range has been reported5. However, it is still too soon to define this receptor from its pharmacology. This issue became more confused when a specific receptor for diadenosine polyphosphates was found. In 1995, we described the existence of independent presynaptic receptors for ATP and diadenosine polyphosphates. We called the receptor for diadenosine polyphosphates a P4 or dinucleotide receptor6. We were following the nomenclature P1, P2, P3 that was established at that time, and we did not call it a P2 receptor because it was not sensitive to any mononucleotides (including ATP, ATP analogues, UTP, UDP, CTP or ITP), nor to P2 receptor antagonists such as suramin, DIDS (4,49-diisohiocyanatostilbene-2,29-disulfonic acid) or PPADS (pyridoxalphosphate-6-azophenyl-29, 49-disulfonic acid). The dinucleotide receptor is only sensitive to dinucleoside polyphosphates and its activation leads to an increase in cytosolic Ca21 concentrations in synaptic terminals by an ionotropic mechanism. This receptor is a receptor-operated Ca21 channel, insensitive to any purine apart from dinucleosides polyphosphates3. These pharmacological data do not permit this
dinucleotide receptor to be included among the P2 receptors described so far. In view of both the evidence for a dinucleotide receptor that is insensitive to mononucleotides and the divergent pharmacological activity of this receptor, it is not appropriate to regard adenine dinucleotides merely as natural analogues or homologues of ATP, and the dinucleotide receptor a variant of the ATP receptor. Thus, we would prefer to use the name dinucleotide receptor rather than any of the other names found in the literature; once cloned, the receptor can then be assigned to a specific family. Jesús Pintor Assistant Professor, E-mail: [email protected] and M. Teresa Miras-Portugal Professor and Chair, Departamento de Bioquímica y Biología Molecular IV, Facultad de Veterinaria, Universidad Complutense de Madrid, 28040 Madrid, Spain. E-mail: [email protected]
Selected references 1 Pintor, J. et al. (1993) Ap4A and ADP-b-S binding to P2 purinoceptors present on rat brain synaptic terminals. Br. J. Pharmacol. 108, 1094–1099 2 Wildman, S.S. et al. (1999) Selectivity of diadenosine polyphosphates for rat P2X receptor subunits. Eur. J. Pharmacol. 367, 119–123 3 Lazarowski, E.R. et al. (1995) Pharmacological selectivity of the cloned human P2U-purinoceptor: potent activation by diadenosine tetraphosphate. Br. J. Pharmacol. 116, 1619–1627 4 Fredholm, B.B. et al. (1997) Towards a revised nomenclature for P1 and P2 receptors. Trends Pharmacol. Sci. 18, 79–82 5 Jimenez, A.I. et al. (1998) Potentiation of adenosine 59-triphosphate calcium responses by diadenosine pentaphosphate in individual rat cerebellar astrocytes. Neurosci. Lett. 246, 109–111 6 Pintor, J. and Miras-Portugal, M.T. (1995) A novel receptor for diadenosine polyphosphates coupled to calcium increase in rat midbrain synaptosomes. Br. J. Pharmacol. 115, 895–902
Editorial policy Most articles published in TiPS are commissioned by the Editor. However, authors who wish to contribute to any section of the journal should contact the Editor with the names of all authors and a point-by-point outline of the proposed article including 10–12 key references. Outlines might also be sent to members of the Advisory Editorial Board. Completed manuscripts submitted without liaison with the TiPS Editorial Office cannot be considered. TiPS readers who wish to suggest that a particular topic be covered are also invited to send their suggestions to Siân Lewis (Editor) at [email protected]
TiPS – April 2000 (Vol. 21)
135
Receptors for diadenosine polyphosphates P2D, P2YApnA, P4 and dinucleotide receptors: are there too many? In 1993, we described the existence of binding sites for diadenosine polyphosphates in the CNS, which we termed P2D receptors, that have a strikingly high affinity for adenine dinucleotides1. Since then, several papers have used this nomenclature (P2D) and other terms (e.g. P2YApnA , P4 and dinucleotide receptor) to define specific receptors for these compounds. Part of this seemingly random and imprecise nomenclature rests on three basic points: (1) an inadequate interpretation of the binding data; (2) the effort of the IUPHAR to include this receptor within the P2X, P2Y nomenclature as a result of the evident structural analogy of dinucleotides to mononucleotides; and (3) the discovery of a specific receptor for diadenosine polyphosphates. In addition, it is important to remember that diadenosine polyphosphates can stimulate both P2X and P2Y receptors in various tissues, and heterologously expressed receptors2,3. The name P2D was coined according to radioligand binding studies and was not based on functional studies so it cannot be considered as a true receptor. It is just a binding site. The IUPHAR committee changed the name P2D to P2YApnA to fit this binding site within one of the two P2X (ligand-gated ion channels) and P2Y (G-protein-coupled) receptor families4. Nevertheless, the lack of functional studies suggests that there is no reason to include the P2D binding site as a P2Y receptor (P2YApnA) because
functional studies regarding its signal transduction mechanism have never been reported. Recently, evidence for a metabotropic dinucleotide receptor that regulates ATP responses in astrocytes with affinity in the nanomolar range has been reported5. However, it is still too soon to define this receptor from its pharmacology. This issue became more confused when a specific receptor for diadenosine polyphosphates was found. In 1995, we described the existence of independent presynaptic receptors for ATP and diadenosine polyphosphates. We called the receptor for diadenosine polyphosphates a P4 or dinucleotide receptor6. We were following the nomenclature P1, P2, P3 that was established at that time, and we did not call it a P2 receptor because it was not sensitive to any mononucleotides (including ATP, ATP analogues, UTP, UDP, CTP or ITP), nor to P2 receptor antagonists such as suramin, DIDS (4,49-diisohiocyanatostilbene-2,29-disulfonic acid) or PPADS (pyridoxalphosphate-6-azophenyl-29, 49-disulfonic acid). The dinucleotide receptor is only sensitive to dinucleoside polyphosphates and its activation leads to an increase in cytosolic Ca21 concentrations in synaptic terminals by an ionotropic mechanism. This receptor is a receptor-operated Ca21 channel, insensitive to any purine apart from dinucleosides polyphosphates3. These pharmacological data do not permit this
dinucleotide receptor to be included among the P2 receptors described so far. In view of both the evidence for a dinucleotide receptor that is insensitive to mononucleotides and the divergent pharmacological activity of this receptor, it is not appropriate to regard adenine dinucleotides merely as natural analogues or homologues of ATP, and the dinucleotide receptor a variant of the ATP receptor. Thus, we would prefer to use the name dinucleotide receptor rather than any of the other names found in the literature; once cloned, the receptor can then be assigned to a specific family. Jesús Pintor Assistant Professor, E-mail: [email protected] and M. Teresa Miras-Portugal Professor and Chair, Departamento de Bioquímica y Biología Molecular IV, Facultad de Veterinaria, Universidad Complutense de Madrid, 28040 Madrid, Spain. E-mail: [email protected]
Selected references 1 Pintor, J. et al. (1993) Ap4A and ADP-b-S binding to P2 purinoceptors present on rat brain synaptic terminals. Br. J. Pharmacol. 108, 1094–1099 2 Wildman, S.S. et al. (1999) Selectivity of diadenosine polyphosphates for rat P2X receptor subunits. Eur. J. Pharmacol. 367, 119–123 3 Lazarowski, E.R. et al. (1995) Pharmacological selectivity of the cloned human P2U-purinoceptor: potent activation by diadenosine tetraphosphate. Br. J. Pharmacol. 116, 1619–1627 4 Fredholm, B.B. et al. (1997) Towards a revised nomenclature for P1 and P2 receptors. Trends Pharmacol. Sci. 18, 79–82 5 Jimenez, A.I. et al. (1998) Potentiation of adenosine 59-triphosphate calcium responses by diadenosine pentaphosphate in individual rat cerebellar astrocytes. Neurosci. Lett. 246, 109–111 6 Pintor, J. and Miras-Portugal, M.T. (1995) A novel receptor for diadenosine polyphosphates coupled to calcium increase in rat midbrain synaptosomes. Br. J. Pharmacol. 115, 895–902
Editorial policy Most articles published in TiPS are commissioned by the Editor. However, authors who wish to contribute to any section of the journal should contact the Editor with the names of all authors and a point-by-point outline of the proposed article including 10–12 key references. Outlines might also be sent to members of the Advisory Editorial Board. Completed manuscripts submitted without liaison with the TiPS Editorial Office cannot be considered. TiPS readers who wish to suggest that a particular topic be covered are also invited to send their suggestions to Siân Lewis (Editor) at [email protected]
TiPS – April 2000 (Vol. 21)
135