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IUPHAR Nomenclature Report

International Union of Pharmacology LVIII: Update on the P2Y G Protein-Coupled Nucleotide Receptors: From Molecular Mechanisms and Pathophysiology to Therapy

Department of Pharmacological Sciences, University of Milan, Milan, Italy (M.P.A., M.F.); Autonomic Neuroscience Centre, Royal Free & University College Medical School, London, United Kingdom (G.B., G.E.K.); Institut de Recherche Interdisciplinaire en Biologic Humanie et Moléculaire and Department of Medicinal Chemistry, Erasme Hospital, University of Libre, Bruxelles, Belgium (J.-M.B.); Department of Pharmacology, University of Cambridge, Cambridge, United Kingdom (E.A.B.); Molecular Pharmacology, Inspire Pharmaceuticals, Inc., Durham, North Carolina (J.L.B.); Department of Physiology and Pharmacology, University of Strathclyde, Strathclyde, United Kingdom (C.K.); Institut National de la Santé et de la Recherche Médicale U.311, Etablissement Francais du Sang-Alsace, Strasbourg, France (C.G.); Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (K.A.J.); and Department of Biochemistry, University of Missouri, Columbia, Missouri (G.A.W.)

Abstract

I. Brief Historical Background of Nucleotides and Their Receptors

II. Molecular Structure of P2Y Receptors

A. Nomenclature and Molecular History of P2Y Receptors

B. Structural Aspects

C. Orphan Receptors Related to P2Y Receptors

III. Second Messenger Systems and Ion Channels

A. Coupling to G Proteins and Intracellular Signaling Pathways

B. P2Y Receptor Coupling to Ion Channels

1. Significance.

2. Approaches to Analysis of the Channel Interactions of Molecularly Identified P2Y Receptors.

3. Voltage-Activated Channels Regulated by P2Y Receptors.

a. Ca2+ channels.

b. The M-current K+ channel.

4. Activation or Inactivation of G Protein-Gated K+ Channels by P2Y Receptors.

5. Conclusions on the Interactions with Identified Ion Channels.

C. Other Potential Interactions with Ion Channels

IV. Principles of P2Y Receptor Classification

V. Agonists and Antagonists

A. Chemical Structure of Agonist and Antagonist Ligands

1. ADP-Preferring P2Y Receptors:

2. ATP-Preferring P2Y Receptor:

3. UTP-Recognizing P2Y Receptors:

4. UDP-Preferring P2Y Receptor:

5. UDP-Sugar-Preferring P2Y Receptor:

B. Molecular Modeling Studies

VI. P2Y Receptor Subtypes

A. P2Y1

B. P2Y2

C. P2Y4

D. P2Y6

E. P2Y11

F. P2Y12

G. P2Y13

H. P2Y14

VII. Receptor Distribution and Function

A. Excitable Cells, Nerves, Glial Cells, and Muscle

B. Immune Cells

C. Endocrine, Adipose, and Exocrine Cells

D. Gut, Liver, and Biliary System

E. Kidney and Bladder

F. Lung

G. Bone and Cartilage

H. Skin

I. Endothelial Cells

J. Special Senses

K. Platelets

1. The P2Y1 Receptor Initiates Platelet Activation and Aggregation.

2. The P2Y12 Receptor Completes and Amplifies Platelet Activation and Aggregation.

VIII. Source of Naturally Occurring Ligands and Mechanisms of Transport and Breakdown

A. Basal Unstimulated Nucleotide Release

1. Constitutive Release of ATP.

2. Constitutive Release of UDP-Glucose.

B. ATP Release by Excitable and Secretory Tissues

C. ATP Release by Nonexcitatory Cells

1. Stress/Hypoxia/Mechanical Stimulation.

a. ATP binding cassette proteins.

b. Stretch and voltage-activated Cl- channels.

2. Nucleotide Release via Vesicular Trafficking.

3. Agonist-Promoted ATP Release.

D. ATP Release by Tissue Damage

E. Extracellular Nucleotide Metabolism

1. Ecto-Nucleoside Triphosphate Diphosphohydrolases.

2. Ecto-Nucleotide Phosphophosphates/Phosphodiesterases.

3. Hydrolysis of UDP-Glucose.

4. Hydrolysis of Diadenosine Polyphosphates.

5. 5'-Nucleotidase.

6. Nucleoside Diphosphokinase

7. Alkaline Phosphatase.

8. Adenylate Kinase.

IX. Interactions between P2Y and Other Receptors

A. Modes of Interaction between G Protein-Coupled Receptors

B. Receptor Dimerization

C. Receptor Cross-Talk

1. G Protein-Coupled Receptors.

2. Receptor Tyrosine Kinases.

3. Ligand-Gated Cation Channels.

X. Gene Activation Regulated by P2Y Receptors

A. Scope of the Gene Activations

B. Synaptically Released ATP Can Act in the Control of Gene Transcription

XI. Potential Therapeutic Applications

There have been many advances in our knowledge about different aspects of P2Y receptor signaling since the last review published by our International Union of Pharmacology subcommittee. More receptor subtypes have been cloned and characterized and most orphan receptors deorphanized, so that it is now possible to provide a basis for a future subdivision of P2Y receptor subtypes. More is known about the functional elements of the P2Y receptor molecules and the signaling pathways involved, including interactions with ion channels. There have been substantial developments in the design of selective agonists and antagonists to some of the P2Y receptor subtypes. There are new findings about the mechanisms underlying nucleotide release and ectoenzymatic nucleotide breakdown. Interactions between P2Y receptors and receptors to other signaling molecules have been explored as well as P2Y-mediated control of gene transcription. The distribution and roles of P2Y receptor subtypes in many different cell types are better understood and P2Y receptor-related compounds are being explored for therapeutic purposes. These and other advances are discussed in the present review.

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