Human Pancreatic Islets Express the Purinergic P2Y₁₁ and P2Y₁₂ Receptors

Introduction

Extracellular adenine nucleotides and their analogues are well-known to stimulate pancreatic β-cell function [1], despite recent evidence for a possible inhibitory function [2]. Attempts to identify the different P2Y receptor subtypes coupled to specific transduction pathways on pancreatic endocrine cells were mainly based on a pharmacological approach using agonists and/or antagonists more specific for a particular receptor subtype. Recent RT-PCR and Western blotting studies from our laboratory [3] point out that pancreatic β-cells, in addition to the previously described P2Y₄ receptor subtype [4], also express the P2Y₁, P2Y₂, P2Y₆, and P2Y₁₂ isoforms.

At present, eight human P2Y receptor subtypes are known that can phylogenetically and structurally be divided into two subgroups. The first one includes P2Y₁, P2Y₂, P2Y₄, P2Y₆, P2Y₁₁ and the second one P2Y₁₂, P2Y₁₃, P2Y₁₄ [5] [6]. Concerning their transduction pathways, P2Y₁, P2Y₂, P2Y₄, P2Y₆ are coupled to phospholipase C and intracellular Ca²⁺mobilization. The P2Y₁₁ receptor, upon stimulation by ATP, leads to a rise in both cAMP and IP₃. The structure and ligand binding characteristics of this less studied receptor subtype have recently been deduced from computational modeling and mutational analysis [7]. Furthermore, it has been proposed as a new target for prevention of acute myocardial infarction [8] and interestingly found to associate functionally with P2Y₁, promoting its internalization [9]. Concerning the second subgroup, P2Y₁₂, P2Y₁₃, P2Y₁₄ are known to be coupled to Gi/o proteins.

G protein-coupled receptors (GPCR) are important targets for the development of antidiabetic drugs and, in pancreatic islets, they are mainly coupled to adenylate cyclase and to phospholipase C [10]. Three main factors prompted us to investigate the possible presence of P2Y₁₁ and P2Y₁₂ receptors as future antidiabetic targets in human pancreatic islets and to determine their cellular localization: 1. An increase in cAMP is responsible for the glucose-dependant insulinotropic effect of GLP-1, the most promising antidiabetic drug presently in development; 2. P2Y agonists induce a glucose-dependent increase in insulin secretion in human pancreatic islets [11]; and 3. The cAMP/PKA pathway intervenes in ATPαS insulin secretory effect in rat islets [12].

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